Targeted chromosomal genomic alterations with modified single stranded oligonucleotides

ABSTRACT

Presented are methods and compositions for targeted chromosomal genomic alterations using modified single-stranded oligonucleotides of the invention have at least one modified nuclease-resistant terminal region comprising phosphorothioate linkages, LNA analogs or 2′-O-Me base analogs.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent Application No. PCT/US01/09761, filed Mar. 27, 2001, which designated the United States and which claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Application Nos. 60/244,989, filed Oct. 30, 2000; 60/208,538, filed Jun. 1, 2000; 60/192,176, filed Mar. 27, 2000; and 60/192,179, filed Mar. 27, 2000.

STATEMENT REGARDING FEDERALLY FUNDED RESEARCH

This invention was made in the course of research under N.I.H. grants R01 HL58563-05 and R01 DK56134-03. The government has certain rights in this invention.

INCORPORATION BY REFERENCE OF MATERIALS FILED ON COMPACT DISC

The present application includes a Sequence Listing filed on a single compact disc (CD-R), filed in duplicate. The Sequence Listing is presented in a single file on each CD-R and is named SequenceListingNapro4. The Sequence Listing was last modified Apr. 18, 2003 at 10:24:54 AM and comprises 930,640 bytes.

FIELD OF THE INVENTION

The technical field of the invention is oligonucleotide-directed repair or alteration of genetic information using novel chemically modified oligonucleotides. Such genetic information is preferably from a eukaryotic organism, i.e. a plant, animal or fungus.

BACKGROUND OF THE INVENTION

A number of methods have been developed specifically to alter the sequence of an isolated DNA in addition to methods to alter directly the genomic information of various plants, fungi and animals, including humans (“gene therapy”). The latter methods generally include the use of viral or plasmid vectors carrying nucleic acid sequences encoding partial or complete portions of a particular protein which is expressed in a cell or tissue to effect the alteration. The expression of the particular protein then results in the desired phenotype. For example, retroviral vectors containing a transgenic DNA sequence allowing for the production of a normal CFTR protein when administered to defective cells are described in U.S. Pat. No. 5,240,846. Others have developed different “gene therapy vectors” which include, for example, portions of adenovirus (Ad) or adeno-associated virus (AAV), or other viruses. The virus portions used are often long terminal repeat sequences which are added to the ends of a transgene of choice along with other necessary control sequences which allow expression of the transgene. See U.S. Pat. Nos. 5,700,470 and 5,139,941. Similar methods have been developed for use in plants. See, for example, U.S. Pat. No. 4,459,355 which describes a method for transforming plants with a DNA vector and U.S. Pat. No. 5,188,642 which describes cloning or expression vectors containing a transgenic DNA sequence which when expressed in plants confers resistance to the herbicide glyphosate. The use of such transgene vectors in any eukaryotic organism adds one or more exogenous copies of a gene, which gene may be foreign to the host, in a usually random fashion at one or more integration sites of the organism's genome at some frequency. The gene which was originally present in the genome, which may be a normal allelic variant, mutated, defective, and/or functional, is retained in the genome of the host.

These methods of gene correction are problematic in that complications which can compromise the health of the recipient, or even lead to death, may result. One such problem is that insertion of exogenous nucleic acid at random location(s) in the genome can have deleterious effects. Another problem with such systems includes the addition of unnecessary and unwanted genetic material to the genome of the recipient, including, for example, viral or other vector remnants, control sequences required to allow production of the transgene protein, and reporter genes or resistance markers. Such remnants and added sequences may have presently unrecognized consequences, for example, involving genetic rearrangements of the recipient genomes. Other problems associated with these types of traditional gene therapy methods include autoimmune suppression of cells expressing an inserted gene due to the presence of foreign antigens. Concerns have also been raised with consumption, especially by humans, of plants containing exogenous genetic material.

More recently, simpler systems involving poly- or oligo-nucleotides have been described for use in the alteration of genomic DNA. These chimeric RNA-DNA oligonucleotides, requiring contiguous RNA and DNA bases in a double-stranded molecule folded by complementarity into a double hairpin conformation, have been shown to effect single basepair or frameshift alterations, for example, for mutation or repair of plant or animal genomes. See, for example, WO 99/07865 and U.S. Pat. No. 5,565,350. In the chimeric RNA-DNA oligonucleotide, an uninterrupted stretch of DNA bases within the molecule is required for sequence alteration of the targeted genome while the obligate RNA residues are involved in complex stability. Due to the length, backbone composition, and structural configuration of these chimeric RNA-DNA molecules, they are expensive to synthesize and difficult to purify. Moreover, if the RNA-containing strand of the chimeric RNA-DNA oligonucleotide is designed so as to direct gene conversion, a series of mutagenic reactions resulting in nonspecific base alteration can result. Such a result compromises the utility of such a molecule in methods designed to alter the genomes of plants and animals, including in human gene therapy applications.

Alternatively, other oligo- or poly-nucleotides have been used which require a triplex forming, usually polypurine or polypyrimidine, structural domain which binds to a DNA helical duplex through Hoogsteen interactions between the major groove of the DNA duplex and the oligonucleotide. Such oligonucleotides may have an additional DNA reactive moiety, such as psoralen, covalently linked to the oligonucleotide. These reactive moieties function as effective intercalation agents, stabilize the formation of a triplex and can be mutagenic. Such agents may be required in order to stabilize the triplex forming domain of the oligonucleotide with the DNA double helix if the Hoogsteen interactions from the oligonucleotide/target base composition are insufficient. See, e.g., U.S. Pat. No. 5,422,251. The utility of these oligonucleotides for directing gene conversion is compromised by a high frequency of nonspecific base changes.

In more recent work, the domain for altering a genome is linked or tethered to the triplex forming domain of the bi-functional oligonucleotide, adding an additional linking or tethering functional domain to the oligonucleotide. See, e.g., Culver et al., Nature Biotechnology 17: 989-93 (1999). Such chimeric or triplex forming molecules have distinct structural requirements for each of the different domains of the complete poly- or oligo-nucleotide in order to effect the desired genomic alteration in either episomal or chromosomal targets.

Other genes, e.g. CFTR, have been targeted by homologous recombination using duplex fragments having several hundred basepairs. See, e.g., Kunzelmann et al., Gene Ther. 3:859-867 (1996). Early experiments to mutagenize an antibiotic resistance indicator gene by homologous recombination used an unmodified DNA oligonucleotide with no functional domains other than a region of complementary sequence to the target See Campbell et al., New Biologist 1: 223-227 (1989). These experiments required large concentrations of the oligonucleotide, exhibited a very low frequency of episomal modification of a targeted exogenous plasmid gene not normally found in the cell and have not been reproduced. However, as shown in the examples herein, we have observed that an unmodified DNA oligonucleotide can convert a base at low frequency which is detectable using the assay systems described herein.

Artificial chromosomes can be useful for the screening purposed identified herein. These molecules are man-made linear or circular DNA molecules constructed from essential cis-acting DNA sequence elements that are responsible for the proper replication and partitioning of natural chromosomes (Murray et al., 1983). The essential elements are: (1) Autonomous Replication Sequences (ARS), (2) Centromeres, and (3) Telomeres.

Yeast artificial chromosomes (YACs) allow large genomic DNA to be modified and used for generating transgenic animals [Burke et al., Science 236:806; Peterson et al., Trends Genet. 13:61 (1997); Choi, et al., Nat. Genet, 4:117-223 (1993), Davies, et al., Biotechnology 11:911-914 (1993), Matsuura, et al., Hum. Mol. Genet., 5:451-459 (1996), Peterson et al., Proc. Natl. Acad. Sci., 93:6605-6609 (1996); and Schedl, et al., Cell, 86:71-82 (1996)]. Other vectors also have been developed for the cloning of large segments of mammalian DNA, including cosmids, and bacteriophage P1 [Sternberg et al., Proc. Natl. Acad. Sci. U.S.A., 87:103-107 (1990)]. YACs have certain advantages over these alternative large capacity cloning vectors [Burke et al., Science, 236:806-812 (1987)]. The maximum insert size is 35-30 kb for cosmids, and 100 kb for bacteriophage P1, both of which are much smaller than the maximal insert for a YAC.

An alternative to YACs are E. coli based cloning systems based on the E. coli fertility factor that have been developed to construct large genomic DNA insert libraries. They are bacterial artificial chromosomes (BACs) and P-1 derived artificial chromosomes (PACs) [Mejia et al., Genome Res. 7:179-186 (1997); Shizuya et al., Proc. Natl. Acad. Sci. 89:8794-8797 (1992); Ioannou et al., Nat. Genet., 6:84-89 (1994); Hosoda et al., Nucleic Acids Res. 18:3863 (1990)]. BACs are based on the E. coli fertility plasmid (F factor); and PACs are based on the bacteriophage P1. These vectors propagate at a very low copy number (1-2 per cell) enabling genomic inserts up to 300 kb in size to be stably maintained in recombination deficient hosts. Furthermore, the PACs and BACs are circular DNA molecules that are readily isolated from the host genomic background by classical alkaline lysis [Birnboim et al., Nucleic Acids Res. 7:1513-1523 (1979].

Oligonucleotides designed for use in the alteration of genetic information are significantly different from oligonucleotides designed for antisense approaches. For example, antisense oligonucleotides are perfectly complementary to and bind an mRNA strand in order to modify expression of a targeted mRNA and are used at high concentration. As a consequence, they are unable to produce a gene conversion event by either mutagenesis or repair of a defect in the chromosomal DNA of a host genome. Furthermore, the backbone chemical composition used in most oligonucleotides designed for use in antisense approaches renders them inactive as substrates for homologous pairing or mismatch repair enzymes and the high concentrations of oligonucleotide required for antisense applications can be toxic with some types of nucleotide modifications. In addition, antisense oligonucleotides must be complementary to the mRNA and therefore, may not be complementary to the other DNA strand or to genomic sequences that span the junction between intron sequence and exon sequence.

A need exists for simple, inexpensive oligonucleotides capable of producing targeted alteration of genetic material such as those described herein as well as methods to identify optimal oligonucleotides that accurately and efficiently alter target DNA.

SUMMARY OF THE INVENTION

Novel, modified single-stranded nucleic acid molecules that direct gene alteration in plants, fungi and animals are identified and the efficiency of alteration is analyzed both in vitro using a cell-free extract assay and in vivo using a yeast cell system. The alteration in an oligonucleotide of the invention may comprise an insertion, deletion, substitution, as well as any combination of these. Site specific alteration of DNA is not only useful for studying function of proteins in vivo, but it is also useful for creating animal models for human disease, and in gene therapy. As described herein, oligonucleotides of the invention target directed specific gene alterations in genomic double-stranded DNA cells. The target DNA can be normal, cellular chromosomal DNA, extrachromosomal DNA present in cells in different forms including, e.g., mammalian artificial chromosomes (MACs), PACs from P-1 vectors, yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), plant artificial chromosomes (PLACs), as well as episomal DNA, including episomal DNA from an exogenous source such as a plasmid or recombinant vector. Many of these artificial chromosome constructs containing human DNA can be obtained from a variety of sources, including, e.g., the Whitehead Institute, and are described, e.g., in Cohen et al., Nature 336:698-701 (1993) and Chumakov, et al., Nature 377:174-297 (1995). The target DNA may be transitionally silent or active. In a preferred embodiment, the target DNA to be altered is the non-transcribed strand of a genomic DNA duplex.

The low efficiency of gene alteration obtained using unmodified DNA oligonucleotides is believed to be largely the result of degradation by nucleases present in the reaction mixture or the target cell. Although different modifications are known to have different effects on the nuclease resistance of oligonucleotides or stability of duplexes formed by such oligonucleotides (see, e.g., Koshkin et al., J. Am. Chem. Soc., 120:13252-3), we have found that it is not possible to predict which of any particular known modification would be most useful for any given alteration event, including for the construction of gene conversion oligonucleotides, because of the interaction of different as yet unidentified proteins during the gene alteration event. Herein, a variety of nucleic acid analogs have been developed that increase the nuclease resistance of oligonucleotides that contain them, including, e.g., nucleotides containing phosphorothioate linkages or 2′-O-methyl analogs. We recently discovered that single-stranded DNA oligonucleotides modified to contain 2′-O-methyl RNA nucleotides or phosphorothioate linkages can enable specific alteration of genetic information at a higher level than either unmodified single-stranded DNA or a chimeric RNA/DNA molecule. See priority applications incorporated herein in their entirety; see also Gamper et al., Nucleic Acids Research 28: 4332-4339 (2000). We also found that additional nucleic acid analogs which increase the nuclease resistance of oligonucleotides that contain them, including, e.g., “locked nucleic acids” or “LNAs”, xylo-LNAs and L-ribo-LNAs; see, for example, Wengel & Nielsen, WO 99/14226; Wengel, WO 00/56748 and Wengel, WO 00/66604; also allow specific targeted alteration of genetic information.

The assay allows for determining the optimum length of the oligonucleotide, optimum sequence of the oligonucleotide, optimum position of the mismatched base or bases, optimum chemical modification or modifications, optimum strand targeted for identifying and selecting the most efficient oligonucleotide for a particular gene alteration event by comparing to a control oligonucleotide. Control oligonucleotides may include a chimeric RNA-DNA double hairpin oligonucleotide directing the same gene alteration event, an oligonucleotide that matches its target completely, an oligonucleotide in which all linkages are phosphorothiolated, an oligonucleotide fully substituted with 2′-O-methyl analogs or an RNA oligonucleotide. Such control oligonucleotides either fail to direct a targeted alteration or do so at a lower efficiency as compared to the oligonucleotides of the invention. The assay further allows for determining the optimum position of a gene alteration event within an oligonucleotide, optimum concentration of the selected oligonucleotide for maximum alteration efficiency by systematically testing a range of concentrations, as well as optimization of either the source of cell extract by testing different organisms or strains, or testing cells derived from different organisms or strains, or cell lines. Using a series of single-stranded oligonucleotides, comprising all RNA or DNA residues and various mixtures of the two, several new structures are identified as viable molecules in nucleotide conversion to direct or repair a genomic mutagenic event. When extracts from mammalian, plant and fungal cells are used and are analyzed using a genetic readout assay in bacteria, single-stranded oligonucleotides having one of several modifications are found to be more active than a control RNA-DNA double hairpin chimera structure when evaluated using an in vitro gene repair assay. Similar results are also observed in vivo using yeast, mammalian, rodent, monkey, human and embryonic cells, including stem cells. Molecules containing various lengths of modified bases were found to possess greater activity than unmodified single-stranded DNA molecules.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides oligonucleotides having chemically modified, nuclease resistant residues, preferably at or near the termini of the oligonucleotides, and methods for their identificaton and use in targeted alteration of genetic material, including gene mutation, targeted gene repair and gene knockout. The oligonucleotides are preferably used for mismatch repair or alteration by changing at least one nucleic acid base, or for frameshift repair or alteration by addition or deletion of at least one nucleic acid base. The oligonucleotides of the invention direct any such alteration, including gene correction, gene repair or gene mutation and can be used, for example, to introduce a polymorphism or haplotype or to eliminate (“knockout”) a particular protein activity.

The oligonucleotides of the invention are designed as substrates for homologous pairing and repair enzymes and as such have a unique backbone composition that differs from chimeric RNA-DNA double hairpin oligonucleotides, antsense oligonucleotides, and/or other poly- or oligo-nucleotides used for altering genomic DNA, such as triplex forming oligonucleotides. The single-stranded oligonucleotides described herein are inexpensive to synthesize and easy to purify. In side-by-side comparisons, an optimized single-stranded oligonucleotide comprising modified residues as described herein is significantly more efficient than a chimeric RNA-DNA double hairpin oligonucleotide in directing a base substitution or frameshift mutation in a cell-free extract assay.

We have discovered that single-stranded oligonucleotides having a DNA domain surrounding the targeted base, with the domain preferably central to the poly- or oligo-nucleotide, and having at least one modified end, preferably at the 3′ terminal region are able to alter a target genetic sequence and with an efficiency that is higher than chimeric RNA-DNA double hairpin oligonucleotides disclosed in U.S. Pat. No. 5,565,350. Oligonucleotides of the invention can efficiently be used to introduce targeted alterations in a genetic sequence of DNA in the presence of human, animal, plant, fungal (including yeast) proteins and in cultured cells of human liver, lung, colon, cervix, kidney, epethelium and cancer cells and in monkey, hamster, rat and mouse cells of different types, as well as embryonic stem cells. Cells for use in the invention include, e.g., fungi including S. cerevisiae, Ustillago maydis and Candida albicans, mammalian, mouse, hamster, rat, monkey, human and embryonic cells including stem cells. The DNA domain is preferably fully complementary to one strand of the gene target, except for the mismatch base or bases responsible for the gene alteration or conversion events. On either side of the preferably central DNA domain, the contiguous bases may be either RNA bases or, preferably, are primarily DNA bases. The central DNA domain is generally at least 8 nucleotides in length. The base(s) targeted for alteration in the most preferred embodiments are at least about 8, 9 or 10 bases from one end of the oligonucleotide.

According to certain embodiments, the termini of the oligonucleotides of the present invention comprise phosphorothioate modifications, LNA backbone modifications, or 2′-O-methyl base analogs, or any combination of these modifications. Oligonucleotides comprising 2′-O-methyl or LNA analogs are a mixed DNA/RNA polymer. These oligonucleotides are, however, single-stranded and are not designed to form a stable internal duplex structure within the oligonucleotide. The efficiency of gene alteration is surprisingly increased with oligonucleotides having internal complementary sequence comprising phosphorothioate modified bases as compared to 2′-O-methyl modifications. This result indicates that specific chemical interactions are involved between the converting oligonucleotide and the proteins involved in the conversion. The effect of other such chemical interactions to produce nuclease resistant termini using modifications other than LNA, phosphorothioate linkages, or 2′-O-methyl analog incorporation into an oligonucleotide can not yet be predicted because the proteins involved in the alteration process and their particular chemical interaction with the oligonucleotide substituents are not yet known and cannot be predicted.

In the examples, correcting oligonucleotides of defined sequence are provided for correction of genes mutated in human diseases. In the tables of these examples, the oligonucleotides of the invention are not limited to the particular sequences disclosed. The oligonucleotides of the invention include extensions of the appropriate sequence of the longer 120 base oligonucleotides which can be added base by base to the smallest disclosed oligonucleotides of 17 bases. Thus the oligonucleotides of the invention include for each correcting change, oligonucleotides of length 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120 with further single-nucleotide additions up to the longest sequence disclosed. Moreover, the oligonucleotides of the invention do not require a symmetrical extension on either side of the central DNA domain. Similarly, the oligonucleotides of the invention as disclosed in the various tables for correction of human diseases contain phosphorothioate linkages, 2′-O-methyl analogs or LNAs or any combination of these modifications just as the assay oligonucleotides do.

The present invention, however, is not limited to oligonucleotides that contain any particular nuclease resistant modification. Oligonucleotides of the invention may be altered with any combination of additional LNAs, phosphorothioate linkages or 2′-O-methyl analogs to maximize conversion efficiency. For oligonucleotides of the invention that are longer than about 17 to about 25 bases in length, internal as well as terminal region segments of the backbone may be altered. Alternatively, simple fold-back structures at each end of a oligonucleotide or appended end groups may be used in addition to a modified backbone for conferring additional nuclease resistance.

The different oligonucleotides of the present invention preferably contain more than one of the aforementioned backbone modifications at each end. In some embodiments, the backbone modifications are adjacent to one another. However, the optimal number and placement of backbone modifications for any individual oligonucleotide will vary with the length of the oligonucleotide and the particular type of backbone modification(s) that are used. If constructs of identical sequence having phosphorothioate linkages are compared, 2, 3, 4, 5, or 6 phosphorothioate linkages at each end are preferred. If constructs of identical sequence having 2′-O-methyl base analogs are compared, 1, 2, 3 or 4 analogs are preferred. The optimal number and type of backbone modifications for any particular oligonucleotide useful for altering target DNA may be determined empirically by comparing the alteration efficiency of the oligonucleotide comprising any combination of the modifications to a control molecule of comparable sequence using any of the assays described herein. The optimal positon(s) for oligonucleotide modifications for a maximally efficient altering oligonucleotide can be determined by testing the various modifications as compared to control molecule of comparable sequence in one of the assays disclosed herein. In such assays, a control molecule includes, e.g., a completely 2′-O-methyl substituted molecule, a completely complementary oligonucleotide, or a chimeric RNA-DNA double hairpin.

Increasing the number of phosphorothioate linkages, LNAs or 2′-O-methyl bases beyond the preferred number generally decreases the gene repair activity of a 25 nucleotide long oligonucleotide. Based on analysis of the concentration of oligonucleotide present in the extract after different time periods of incubation, it is believed that the terminal modifications impart nuclease resistance to the oligonucleotide thereby allowing it to survive within the cellular environment. However, this may not be the only possible mechanism by which such modifications confer greater efficiency of conversion. For example, as disclosed herein, certain modifications to oligonucleotides confer a greater improvement to the efficiency of conversion than other modifications.

Efficiency of conversion is defined herein as the percentage of recovered substate molecules that have undergone a conversion event. Depending on the nature of the target genetic material, e.g. the genome of a cell, efficiency could be represented as the proportion of cells or clones containing an extrachromosomal element that exhibit a particular phenotype. Alternatively, representative samples of the target genetic material can be sequenced to determine the percentage that have acquired the desire change. The oligonucleotides of the invention in different embodiments can alter DNA one, two, three, four, five, six, seven, eight, nine, ten, twelve, fifteen, twenty, thirty, and fifty or more fold more than control oligonucleotides. Such control oligonucleotides are oligonucleotides with fully phosphorothiolated linkages, oligonucleotides that are fully substituted with 2′-O-methyl analogs, a perfectly matched oligonucleotide that is fully complementary to a target sequence or a chimeric DNA-RNA double hairpin oligonucleotide such as disclosed in U.S. Pat. No. 5,565,350.

In addition, for a given oligonucleotide length, additional modifications interfere with the ability of the oligonucleotide to act in concert with the cellular recombination or repair enzyme machinery which is necessary and required to mediate a targeted substitution, addition or deletion event in DNA. For example, fully phosphorothiolated or fully 2-O-methylated molecules are inefficient in targeted gene alteration.

The oligonucleotides of the invention as optimized for the purpose of targeted alteration of genetic material, including gene knockout or repair, are different in structure from antisense oligonucleotides that may possess a similar mixed chemical composition backbone. The oligonucleotides of the invention differ from such antisense oligonucleotides in chemical composition, structure, sequence, and in their ability to alter genomic DNA. Significantly, antisense oligonucleotides fail to direct targeted gene alteration. The oligonucleotides of the invention may target either the Watson or the Crick strand of DNA and can include any component of the genome including, for example, intron and exon sequences. The preferred embodiment of the invention is a modified oligonucleotide that binds to the non-transcribed strand of a genomic DNA duplex. In other words, the preferred oligonucleotides of the invention target the sense strand of the DNA, i.e. the oligonucleotides of the invention are complementary to the non-transcribed strand of the target duplex DNA. The sequence of the non-transcribed strand of a DNA duplex is found in the mRNA produced from that duplex, given that mRNA uses uracil-containing nucleotides in place of thymine-containing nucleotides.

Moreover, the initial observation that single-stranded oligonucleotides comprising these modifications and lacking any particular triplex forming domain have reproducibly enhanced gene repair activity in a variety of assay systems as compared to a chimeric RNA-DNA double-stranded hairpin control or single-stranded oligonucleotides comprising other backbone modifications was surprising. The single-stranded molecules of the invention totally lack the complementary RNA binding structure that stabilizes a normal chimeric double-stranded hairpin of the type disclosed in U.S. Pat. No. 5,565,350 yet is more effective in producing targeted base conversion as compared to such a chimeric RNA-DNA double-stranded hairpin. In addition, the molecules of the invention lack any particular triplex forming domain involved in Hoogsteen interactions with the DNA double helix and required by other known oligonucleotides in other oligonucleotide dependant gene conversion systems. Although the lack of these functional domains was expected to decrease the efficiency of an alteration in a sequence, just the opposite occurs: the efficiency of sequence alteration using the modified oligonucleotides of the invention is higher than the efficiency of sequence alteration using a chimeric RNA-DNA hairpin targeting the same sequence alteration. Moreover, the efficiency of sequence alteration or gene conversion directed by an unmodified oligonucleotide is many times lower as compared to a control chimeric RNA-DNA molecule or the modified oligonucleotides of the invention targeting the same sequence alteration. Similarly, molecules containing at least 3 2′-O-methyl base analogs are about four to five fold less efficient as compared to an oligonucleotide having the same number of phosphorothioate linkages.

The oligonucleotides of the present invention for alteration of a single base are about 17 to about 121 nucleotides in length, preferably about 17 to about 74 nucleotides in length. Most preferably, however, the oligonucleotides of the present invention are at least about 25 bases in length, unless there are self-dimerization structures within the oligonucleotide. If the oligonucleotide has such an unfavorable structure, lengths longer than 35 bases are preferred. Oligonucleotides with modified ends both shorter and longer than certain of the exemplified, modified oligonucleotides herein function as gene repair or gene knockout agents and are within the scope of the present invention.

Once an oligomer is chosen, it can be tested for its tendency to self-dimerize, since self-dimerization may result in reduced efficiency of alteration of genetic information. Checking for self-dimenzation tendency can be accomplished manually or, more preferably, by using a software program. One such program is Oligo Analyzer 2.0, available through Integrated DNA Technologies (Coralville, Iowa 52241); this program is available for use on the world wide web at the Integrated DNA Technologies web site.

For each oligonucleotide sequence input into the program, Oligo Analyzer 2.0 reports possible seif-dimerized duplex forms, which are usually only partially duplexed, along with the free energy change associated with such self-dimerization. Delta G-values that are negative and large in magnitude, indicating strong seif-dimerization potential, are automatically flagged by the software as “bad”. Another software program that analyzes oligomers for pair dimer formation is Primer Select from DNASTAR, Inc., 1228 S. Park St., Madison, Wis. 53715, Phone: (608) 258-7420 If the sequence is subject to significant self-dimerization, the addition of further sequence flanking the “repair” nucleotide can improve gene correction frequency.

Generally, the oligonucleotides of the present invention are identical in sequence to one strand of the target DNA, which can be either strand of the target DNA, with the exception of one or more targeted bases positioned within the DNA domain of the oligonucleotide, and preferably toward the middle between the modified terminal regions. Preferably, the difference in sequence of the oligonucleotide as compared to the targeted genomic DNA is located at about the middle of the oligonucleotide sequence. In a preferred embodiment, the oligonucleotides of the invention are complementary to the non-transcribed strand of a duplex. In other words, the preferred oligonucleotides target the sense strand of the DNA, i.e. the oligonucleotides of the invention are preferably complementary to the strand of the target DNA the sequence of which is found in the mRNA.

The oligonucleotides of the invention can include more than a single base change. In an oligonucleotide that is about a 70-mer, with at least one modified residue incorporated on the ends, as disclosed herein, multiple bases can be simultaneously targeted for change. The target bases may be up to 27 nucleotides apart and may not be changed together in all resultant plasmids in all cases. There is a frequency distribution such that the closer the target bases are to each other in the central DNA domain within the oligonucleotides of the invention, the higher the frequency of change in a given cell. Target bases only two nucleotides apart are changed together in every case that has been analyzed. The farther apart the two target bases are, the less frequent the simultaneous change. Thus, oligonucleotides of the invention may be used to repair or alter multiple bases rather than just one single base. For example, in a 74-mer oligonucleotide having a central base targeted for change, a base change event up to about 27 nucleotides away can also be effected. The positions of the altering bases within the oligonucleotide can be optimized using any one of the assays described herein. Preferably, the altering bases are at least about 8 nucleotides from one end of the oligonucleotide.

The oligonucleotides of the present invention can be introduced into cells by any suitable means. According to certain preferred embodiments, the modified oligonucleotides may be used alone. Suitable means, however, include the use of polycations, cationic lipids, liposomes, polyethylenimine (PEI), electroporation, biolistics, microinjecton and other methods known in the art to facilitate cellular uptake. According to certain preferred embodiments of the present invention, the isolated cells are treated in culture according to the methods of the invention, to mutate or repair a target gene. Modified cells may then be reintroduced into the organism as, for example, in bone marrow having a targeted gene. Alternatively, modified cells may be used to regenerate the whole organism as, for example, in a plant having a desired targeted genomic change. In other instances, targeted genomic alteration, including repair or mutagenesis, may take place in vivo following direct administration of the modified, single-stranded oligonucleotides of the invention to a subject.

The single-stranded, modified oligonucleotides of the present invention have numerous applications as gene repair, gene modification, or gene knockout agents. Such oligonucleotides may be advantageously used, for example, to introduce or correct multiple point mutations. Each mutation leads to the addition, deletion or substitution of at least one base pair. The methods of the present invention offer distinct advantages over other methods of altering the genetic makeup of an organism, in that only the individually targeted bases are altered. No additional foreign DNA sequences are added to the genetic complement of the organism. Such agents may, for example, be used to develop plants or animals with improved traits by rationally changing the sequence of selected genes in cultured cells. Modified cells are then cloned into whole plants or animals having the altered gene. See, e.g., U.S. Pat. No. 6,046,380 and U.S. Pat. No. 5,905,185 incorporated herein by reference. Such plants or animals produced using the compositions of the invention lack additional undesirable selectable markers or other foreign DNA sequences. Targeted base pair substitution or frameshift mutations introduced by an oligonucleotide in the presence of a cell-free extract also provides a way to modify the sequence of extrachromosomal elements, including, for example, plasmids, cosmids and artificial chromosomes. The oligonucleotides of the invention also simplify the production of transgenic animals having particular modified or inactivated genes. Altered animal or plant model systems such as those produced using the methods and oligonucleotides of the invention are invaluable in determining the function of a gene and in evaluating drugs. The oligonucleotides and methods of the present invention may also be used for gene therapy to correct mutations causative of human diseases.

The purified oligonucleotide compositions may be formulated in accordance with routine procedures as a pharmaceutical composition adapted for bathing cells in culture, for microinjecton into cells in culture, and for intravenous administration to human beings or animals. Typically, compositions for cellular administration or for intravenous administration into animals, including humans, are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anaesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients will be supplied either separately or mixed together in unit dosage form, for example, as a dry, lyophilized powder or water-free concentrate. The composition may be stored in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent in activity units. Where the composition is administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade “water for injection” or saline. Where the composition is to be administered by injection, an ampule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.

Pharmaceutical compositions of this invention comprise the compounds of the present invention and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable ingredient, excipient, carrier, adjuvant or vehicle.

The oligonucleotides of the invention are preferably administered to the subject in the form of an injectable composition. The composition is preferably administered parenterally, meaning intravenously, intraarterially, intrathecally, interstitially or intracavitarilly. Pharmaceutical compositions of this invention can be administered to mammals including humans in a manner similar to other diagnostic or therapeutic agents. The dosage to be administered, and the mode of administration will depend on a variety of factors including age, weight, sex, condition of the subject and genetic factors, and will ultimately be decided by medical personnel subsequent to experimental determinations of varying dosage as described herein. In general, dosage required for correction and therapeutic efficacy will range from about 0.001 to 50,000 μg/kg, preferably between 1 to 250 μg/kg of host cell or body mass, and most preferably at a concentration of between 30 and 60 micromolar.

For cell administration, direct injection into the nucleus, biolistic bombardment, electroporation, liposome transfer and calcium phosphate precipitation may be used. In yeast, lithium acetate or spheroplast transformation may also be used. In a preferred method, the administration is performed with a liposomal transfer compound, e.g., DOTAP (Boehringer-Mannheim) or an equivalent such as lipofectin. The amount of the oligonucleotide used is about 500 nanograms in 3 micrograms of DOTAP per 100,000 cells. For electroporation, between 20 and 2000 nanograms of oligonucleotide per million cells to be electroporated is an appropriate range of dosages which can be increased to improve efficiency of genetic alteration upon review of the appropriate sequence according to the methods described herein.

Another aspect of the invention is a kit comprising at least one oligonucleotide of the invention. The kit may comprise an addition reagent or article of manufacture. The additional reagent or article of manufacture may comprise a cell extract, a cell, or a plasmid, such as one of those disclosed in the Figures herein, for use in an assay of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Flow diagram for the generation of modified single-stranded oligonucleotides. The upper strands of chimeric oligonucleotides I and II are separated into pathways resulting in the generation of single-stranded oligonucleotides that contain (A) 2′-O-methyl RNA nucleotides or (B) phosphorothioate linkages. Fold changes in repair activity for correction of kan^(s) in the HUH7 cell-free extract are presented in parenthesis. HUH-7 cells are described in Nakabayashi et al., Cancer Research 42: 3858-3863 (1982). Each single-stranded oligonucleotide is 25 bases in length and contains a G residue mismatched to the complementary sequence of the kan^(s) gene. The numbers 3, 6, 8, 10, 12 and 12.5 respectively indicate how many phosphorothioate linkages (S) or 2′-O-methyl RNA nucleotides (R) are at each end of the molecule. Hence oligo 12S/25G contains an all phosphorothioate backbone, displayed as a dotted line. Smooth lines indicate DNA residues, wavy lines indicate 2′-O-methyl RNA residues and the carat indicates the mismatched base site (G). FIG. 1(C) provides a schematic plasmid indicating the sequence of the kan chimeric double-stranded hairpin oligonucleotide (left; SEQ ID NO:4341) and the sequence the tet chimeric double-stranded hairpin oligonucleotide used in other experiments (SEQ ID NO:4342). FIG. 1(D) provides a flow chart of a kan experiment in which a chimeric double-stranded hairpin oligonucleotide (SEQ ID NO:4341) is used. In FIG. 1(D), the Kan mutant sequence corresponds to SEQ ID NO:4343 and SEQ ID NO:4344: the Kan converted sequence corresponds to SEQ ID NO:4345 and SEQ ID NO:4346; the mutant sequence in the sequence trace corresponds to SEQ ID NO:4347 and the converted sequences in the sequence trace correspond to SEQ ID NO:4348.

FIG. 2. Genetic readout system for correction of a point mutation in plasmid pK^(s)m4021. A mutant kanamycin gene harbored in plasmid pK^(s)m4021 is the target for correction by oligonucleotides. The mutant G is converted to a C by the action of the oligo. Corrected plasmids confer resistance to kanamycin in E.coli (DH10B) after electroporation leading to the genetic readout and colony counts. The wild type sequence corresponds to SEQ ID NO:4349.

FIG. 3. Target plasmid and sequence correction of a frameshift mutation by chimeric and single-stranded oligonucleotides. (A) Plasmid pT^(s)Δ208 contains a single base deletion mutation at position 208 rendering it unable to confer tet resistance. The target sequence presented below indicates the insertion of a T directed by the oligonucleotides to re-establish the resistant phenotype. (B) DNA sequence confirming base insertion directed by Tet 3S/25G; the yellow highlight indicates the position of frame shift repair. The wild type sequence corresponds to SEQ ID NO:4350, the mutant sequence corresponds to SEQ ID NO:4351 and the converted sequence corresponds to SEQ ID NO:4352. The control sequence in the sequence trace corresponds to SEQ ID NO:4353 and the 3S/25A sequence in the sequence trace corresponds to SEQ ID NO:4354.

FIG. 4. DNA sequences of representative kan^(r) colonies. Confirmation of sequence alteration directed by the indicated molecule is presented along with a table outlining codon distribution. Note that 10S/25G and 12S/25G elicit both mixed and unfaithful gene repair. The number of clones sequenced is listed in parentheses next to the designation for the single-stranded oligonucleotide. A plus (+) symbol indicates the codon identified while a figure after the (+) symbol indicates the number of colonies with a particular sequence. TAC/TAG indicates a mixed peak. Representative DNA sequences are presented below the table with yellow highlighting altered residues. The sequences in the sequence trace have been assigned numbers as follows: 3S/25G, 6S/25G and 8S/25G correspond to SEQ ID NO:4355, 10S/25G corresponds to SEQ ID NO:4356, 25S/25G on the lower left corresponds to SEQ ID NO:4357 and 25S/25G on the lower right corresponds to SEQ ID NO:4358.

FIG. 5. Gene correction in HeLa cells. Representative oligonucleotides of the invention are co-transfected with the pCMVneo(⁻)FlAsH plasmid (shown in FIG. 9) into HeLa cells. Ligand is diffused into cells after co-transfection of plasmid and oligonucleotides. Green fluorescence indicates gene correction of the mutation in the antibiotic resistance gene. Correction of the mutation results in the expression of a fusion protein that carries a marker ligand binding site and when the fusion protein binds the ligand, a green fluorescence is emitted. The ligand is produced by Aurora Biosciences and can readily diffuse into cells enabling a measurement of corrected protein function; the protein must bind the ligand directly to induce fluorescence. Hence cells bearing the corrected plasmid gene appear green while “uncorrected” cells remain colorless.

FIG. 6. Z-series imaging of corrected cells. Serial cross-sections of the HeLa cell represented in FIG. 5 are produced by Zeiss 510 LSM confocal microscope revealing that the fusion protein is contained within the cell.

FIG. 7. Hygromycin-eGFP target plasmids. (A) Plasmid pAIJRHYG(ins)GFP contains a single base insertion mutation between nucleotides 136 and 137, at codon 46, of the Hygromycin B coding sequence (cds) which is transcribed from the constitutive ADH1 promoter. The target sequence presented below indicates the deletion of an A and the substitution of a C for a T directed by the oligonucleotides to re-establish the resistant phenotype. In FIG. 7A, the sequence of the normal allele corresponds to SEQ ID NO:4359, the sequence of the target/existing mutation corresponds to SEQ ID NO:4360 and the sequence of the desired alteration corresponds to SEQ ID NO:4361. (B) Plasmid pAURHYG(rep)GFP contains a base substitution mutation introducing a G at nucleotide 137, at codon 46, of the Hygromycin B coding sequence (cds). The target sequence presented below the diagram indicates the amino acid conservative replacement of G with C, restoring gene function. In FIG. 7B, the sequence of the normal allele corresponds to SEQ ID NO:4359, the sequence of the target/existing mutation corresponds to SEQ ID NO:4362 and the sequence of the desired alteration corresponds to SEQ ID NO:4361.

FIG. 8. Oligonucleotides for correction of hygromycin resistance gene. The sequence of the oligonucleotides used in experiments to assay correction of a hygromycin resistance gene are shown. DNA residues are shown in capital letters, RNA residues are shown in lowercase and nucleotides with a phosphorothioate backbone are capitalized and underlined. In FIG. 8, the sequence of HygE3T/25 corresponds to SEQ ID NO:4363, the sequence of HygE3T/74 corresponds to SEQ ID NO:4364, the sequence of HygE3T/74a corresponds to SEQ ID NO:4365, the sequence of HygGG/Rev corresponds to SEQ ID NO:4366 and the sequence of Kan70T corresponds to SEQ ID NO:4367.

FIG. 9. pAURNeo(−)FlAsH plasmid. This figure describes the plasmid structure, target sequence, oligonucleotides, and the basis for detection of the gene alteration event by fluorescence. In FIG. 9, the sequence of the Neo/kan target mutant corresponds to SEQ ID NO:4343 and SEQ ID NO:4344, the converted sequence corresponds to SEQ ID NO:4345 and SEQ ID NO:4346 and the FIAsH peptide sequence corresponds to SEQ ID NO:4367.

FIG. 10. pYESHyg(x)eGFP plasmid. This plasmid is a construct similar to the pAURHyg(x)eGFP construct shown in FIG. 7, except the promoter is the inducible GAL1 promoter. This promoter is inducible with galactose, leaky in the presence of raffinose, and repressed in the presence of dextrose.

The following examples are provided by way of illustration only, and are not intended to limit the scope of the invention disclosed herein.

EXAMPLE 1 Assay Method for Base Alteration and Preferred Oligonucleotide Selection

In this example, single-stranded and double-hairpin oligonucleotides with chimeric backbones (see FIG. 1 for structures (A and B) and sequences (C and D) of assay oligonucleotides) are used to correct a point mutation in the kanamycin gene of pK^(s)m4021 (FIG. 2) or the tetracycline gene of pT^(s)Δ208 (FIG. 3). All kan oligonucleotides share the same 25 base sequence surrounding the target base identified for change, just as all tet oligonucleotides do. The sequence is given in FIG. 1C and FIG. 1D. Each plasmid contains a functional ampicillin gene. Kanamycin gene function is restored when a G at position 4021 is converted to a C (via a substitution mutation); tetracycline gene function is restored when a deletion at position 208 is replaced by a C (via frameshift mutation). A separate plasmid, pAURNeo(−)FlAsH (FIG. 9), bearing the kan^(s) gene is used in the cell culture experiments. This plasmid was constructed by inserting a synthetic expression cassette containing a neomycin phosphotransferase (kanamycin resistance) gene and an extended reading frame that encodes a receptor for the FlAsH ligand into the pAUR123 shuttle vector (Panvera Corp., Madison, Wis.). The resulting construct replicates in S. cerevisiae at low copy number, confers resistance to aureobasidinA and constitutively expresses either the Neo+/FlAsH fusion product (after alteration) or the truncated Neo−/FlAsH product (before alteration) from the ADH1 promoter. By extending the reading frame of this gene to code for a unique peptide sequence capable of binding a small ligand to form a fluorescent complex, restoration of expression by correction of the stop codon can be detected in real time using confocal microscopy. Additional constructs can be made to test additional gene alteration events.

We also construct three mammalian expression vectors, pHyg(rep)eGFP, pHyg(Δ)eGFP, pHyg(ins)eGFP, that contain a substitution mutation at nucleotide 137 of the hygromycin-B coding sequence. (rep) indicates a T137→G replacement, (Δ) represents a deletion of the G137 and (ins) represents an A insertion between nucleotides 136 and 137. All point mutations create a nonsense termination codon at residue 46. We use pHygEGFP plasmid (Invitrogen, CA) DNA as a template to introduce the mutations into the hygromycin-eGFP fusion gene by a two step site-directed mutagenesis PCR protocol. First, we generate overlapping 5′ and a 3′ amplicons surrounding the mutation site by PCR for each of the point mutation sites. A 215 bp 5′ amplicon for the (rep), (Δ) or (ins) was generated by polymerization from oligonucleotide primer HygEGFPf (5′-AATACGACTCACTATAGG-3′; SEQ ID NO:4369) to primer Hygrepr (5′GACCTATCCACGCCCTCC-3′: SEQ ID NO:4370), HygΔr (5′-GACTATCCACGCCCTCC-3′; SEQ ID NO:4371), or Hyginsr (5′-GACATTATCCACGCCCTCC-3α; SEQ ID NO:4372), respectively. We generate a 300 bp 3′ amplicon for the (rep), (Δ) or (ins) by polymerization from oligonucleotide primers Hygrepf (5′-CTGGGATAGGTCCTGCGG-3′; SEQ ID NO:4373), HygΔf(5′-CGTGGATAGTCCTGCGG-3+; SEQ ID NO:4374), Hyginsf (5′-CGTGGATAATGTCCTGCGG-3′; SEQ ID NO:4375), respectively to primer HygEGFPr (5′-AAATCACGCCATGTAGTG-3′; SEQ ID NO:4376). We mix 20 ng of each of the resultant 5′ and 3′ overlapping amplicon mutation sets and use the mixture as a template to amplify a 523 bp fragment of the Hygromycin gene spanning the KpnI and RsrII restriction endonuclease sites. We use the Expand PCR system (Roche) to generate all amplicons with 25 cycles of denaturing at 94° C. for 10 seconds, annealing at 55° C. for 20 seconds and elongation at 68° C. for 1 minute. We digest 10 μg of vector pHygEGFP and 5 μg of the resulting fragments for each mutation with KpnI and RsrII (NEB) and gel purify the fragment for enzymatic ligation. We ligate each mutated insert into pHygEGFP vector at 3:1 molar ration using T4 DNA ligase (Roche). We screen clones by restriction digest, confirm the mutation by Sanger dideoxy chain termination sequencing and purify the plasmid using a Qiagen maxiprep kit.

Oligonucleotide synthesis and cells. Chimeric oligonucleotides and single-stranded oligonucleotides (including those with the indicated modifications) are synthesized using available phosphoramidites on controlled pore glass supports. After deprotecton and detachment from the solid support, each oligonucleotide is gel-purified using, for example, procedures such as those described in Gamper et al., Biochem. 39, 5808-5816 (2000) and the concentrations determined spectrophotometrically (33 or 40 μg/ml per A₂₆₀ unit of single-stranded or hairpin oligomer). HUH7 cells are grown in DMEM, 10% FBS, 2 mM glutamine, 0.5% pen/strep. The E.coli strain, DH10B, is obtained from Life Technologies (Gaithersburg, Md.); DH10B cells contain a mutation in the RECA gene (recA).

Cell-free extracts. We prepare cell-free extracts from HUH7 cells or other mammalian cells, as follows. We employ this protocol with essentially any mammalian cell including, for example, H1299 cells (human epithelial carcinoma, non-small cell lung cancer), C127I (immortal murine mammary epithelial cells), MEF (mouse embryonic fibroblasts), HEC-1-A (human uterine carcinoma), HCT15 (human colon cancer), HCT116 (human colon carcinoma), LoVo (human colon adenocarcinoma), and HeLa (human cervical carcinoma). We harvest approximately 2×10⁸ cells. We then wash the cells immediately in cold hypotonic buffer (20 mM HEPES, pH7.5; 5 mM KCl; 1.5 mM MgCl₂; 1 mM DTT) with 250 mM sucrose. We then resuspend the cells in cold hypotonic buffer without sucrose and after 15 minutes we lyse the cells with 25 strokes of a Dounce homogenizer using a tight fitting pestle. We incubate the lysed cells for 60 minutes on ice and centrifuge the sample for 15 minutes at 12000×g. The cytoplasmic fraction is enriched with nuclear proteins due to the extended co-incubation of the fractions following cell breakage. We then immediately aliquote and freeze the supernatant at −80° C. We determine the protein concentration in the extract by the Bradford assay.

We also perform these experiments with cell-free extracts obtained from fungal cells, including, for example, S. cerevisiae (yeast), Ustilago maydis, and Candida albicans. For example, we grow yeast cells into log phase in 2L YPD medium for 3 days at 30° C. We then centrifuge the cultures at 5000×g, resuspend the pellets in a 10% sucrose, 50 mM Tris, 1 mM EDTA lysis solution and freeze them on dry ice. After thawing, we add KCl, spermidine and lyticase to final concentrations of 0.25 mM, 5 mM and 0.1 mg/ml, respectively. We incubate the suspension on ice for 60 minutes, add PMSF and Triton X100 to final concentrations of 0.1 mM and 0.1% and continue to incubate on ice for 20 minutes. We centrifuge the lysate at 3000×g for 10 minutes to remove larger debris. We then remove the supernatant and clarify it by centrifuging at 30000×g for 15 minutes. We then add glycerol to the clarified extract to a concentration of 10% (v/v) and freeze aliquots at −80° C. We determine the protein concentration of the extract by the Bradford assay.

Reaction mixtures of 50 μl are used, consisting of 10-30 μg protein of cell-free extract, which can be optionally substituted with purified proteins or enriched fractions, about 1.5 μg chimeric double-hairpin oligonucleotide or 0.55 μg single-stranded molecule (3S/25G or 6S/25G, see FIG. 1), and 1 μg of plasmid DNA (see FIGS. 2 and 3) in a reaction buffer of 20 mM Tris, pH 7.4, 15 mM MgCl₂, 0.4 mM DTT, and 1.0 mM ATP. Reactions are initiated with extract and incubated at 30° C. for 45 min. The reaction is stopped by placing the tubes on ice and then immediately deproteinized by two phenol/chloroform (1:1) extractions. Samples are then ethanol precipitated. The nucleic acid is pelleted at 15,000 r.p.m. at 4° C. for 30 min., is washed with 70% ethanol, resuspended in 50 μl H₂O, and is stored at −20° C. 5 μl of plasmid from the resuspension (˜100 ng) was transfected in 20 μl of DH10B cells by electroporation (400 V, 300 μF, 4 kΩ) in a Cell-Porator apparatus (Life Technologies). After electroporation, cells are transferred to a 14 ml Falcon snap-cap tube with 2 ml SOC and shaken at 37° C. for 1 h. Enhancement of final kan colony counts is achieved by then adding 3 ml SOC with 10 μg/ml kanamycin and the cell suspension is shaken for a further 2 h at 37° C. Cells are then spun down at 3750×g and the pellet is resuspended in 500 μl SOC. 200 μl is added undiluted to each of two kanamycin (50 μg/ml) agar plates and 200 μl of a 10⁵ dilution is added to an ampicillin (100 μg/ml) plate. After overnight 37° C. incubation, bacterial colonies are counted using an Accucount 1000 (Biologics). Gene conversion effectiveness is measured as the ratio of the average of the kan colonies on both plates per amp colonies multiplied by 10⁻⁵ to correct for the amp dilution.

The following procedure can also be used. 5 μl of resuspended reaction mixtures (total volume 50 μl) are used to transform 20 μl aliquots of electro-competent ΔH10B bacteria using a Cell-Porator apparatus (Life Technologies). The mixtures are allowed to recover in 1 ml SOC at 37° C. for 1 hour at which time 50 μg/ml kanamycin or 12 μg/ml tetracycline is added for an additional 3 hours. Prior to plating, the bacteria are pelleted and resuspended in 200 μl of SOC. 100 μl aliquots are plated onto kan or tet agar plates and 100 μl of a 10⁻⁴ dilution of the cultures are concurrently plated on agar plates containing 100 μg/ml of ampicillin. Plating is performed in triplicate using sterile Pyrex beads. Colony counts are determined by an Accu-count 1000 plate reader (Biologics). Each plate contains 200-500 ampicillin resistant colonies or 0-500 tetracycline or kanamycin resistant colonies. Resistant colonies are selected for plasmid extraction and DNA sequencing using an ABI Prism kit on an ABI 310 capillary sequencer (PE Biosystems).

Chimeric single-stranded oligonucleotides. In FIG. 1 the upper strands of chimeric oligonucleotides I and II are separated into pathways resulting in the generation of single-stranded oligonucleotides that contain (FIG. 1A) 2′-O-methyl RNA nucleotides or (FIG. 1B) phosphorothioate linkages. Fold changes in repair activity for correction of kan^(s) in the HUH7 cell-free extract are presented in parenthesis. Each single-stranded oligonucleotide is 25 bases in length and contains a G residue mismatched to the complementary sequence of the kan^(s) gene.

Molecules bearing 3, 6, 8, 10 and 12 phosphorothioate linkages in the terminal regions at each end of a backbone with a total of 24 linkages (25 bases) are tested in the kan^(s) system. Alternatively, molecules bearing 2, 4, 5, 7, 9 and 11 in the terminal regions at each end are tested. The results of one such experiment, presented in Table 1 and FIG. 1B, illustrate an enhancement of correction activity directed by some of these modified structures. In this illustrative example, the most efficient molecules contained 3 or 6 phosphorothioate linkages at each end of the 25-mer; the activities are approximately equal (molecules IX and X with results of 3.09 and 3.7 respectively). A reduction in alteration activity may be observed as the number of modified linkages in the molecule is further increased. Interestingly, a single-strand molecule containing 24 phosphorothioate linkages is minimally active suggesting that this backbone modification when used throughout the molecule supports only a low level of targeted gene repair or alteration. Such a non-altering, completely modified molecule can provide a baseline control for determining efficiency of correction for a specific oligonucleotide molecule of known sequence in defining the optimum oligonucleotide for a particular alteration event.

The efficiency of gene repair directed by phosphorothioate-modified, single-stranded molecules, in a length dependent fashion, led us to examine the length of the RNA modification used in the original chimera as it relates to correction. Construct III represents the “RNA-containing” strand of chimera I and, as shown in Table 1 and FIG. 2A, it promotes inefficient gene repair. But, as shown in the same figure, reducing the RNA residues on each end from 10 to 3 increases the frequency of repair. At equal levels of modification, however, 25-mers with 2′-O-methyl ribonucleotides were less effective gene repair agents than the same oligomers with phosphorothioate linkages. These results reinforce the fact that an RNA containing oligonucleotide is not as effective in promoting gene repair or alteration as a modified DNA oligonucleotide.

Repair of the kanamycin mutation requires a G→C exchange. To confirm that the specific desired correction alteration was obtained, colonies selected at random from multiple experiments are processed and the isolated plasmid DNA is sequenced. As seen in FIG. 4, colonies generated through the action of the single-stranded molecules 3S/25G (IX), 6S/25G (X) and 8S/25G (XI) respectively contained plasmid molecules harboring the targeted base correction. While a few colonies appeared on plates derived from reaction mixtures containing 25-mers with 10 or 12 thioate linkages on both ends, the sequences of the plasmid molecules from these colonies contain nonspecific base changes. In these illustrative examples, the second base of the codon is changed (see FIG. 3). These results show that modified single-strands can direct gene repair, but that efficiency and specificity are reduced when the 25-mers contain 10 or more phosphorothioate linkages at each end.

In FIG. 1, the numbers 3, 6, 8, 10, 12 and 12.5 respectively indicate how many phosphorothioate linkages (S) or 2′-O-methyl RNA nucleotides (R) are at each end of the exemplified molecule although other molecules with 2, 4, 5, 7, 9 and 11 modifications at each end can also be tested. Hence oligo 12S/25G represents a 25-mer oligonucleotide which contains 12 phosphorothioate linkages on each side of the central G target mismatch base producing a fully phosphorothioate linked backbone, displayed as a dotted line. The dots are merely representative of a linkage in the figure and do not depict the actual number of linkages of the oligonucleotide. Smooth lines indicate DNA residues, wavy lines indicate 2′-O-methyl RNA residues and the carat indicates the mismatched base site (G).

Correction of a mutant kanamycin gene in cultured mammalian cells. The experiments are performed using different mammalian cells, including, for example, 293 cells (transformed human primary kidney cells), HeLa cells (human cervical carcinoma), and H1299 (human epithelial carcinoma, non-small cell lung cancer). HeLa cells are grown at 37° C. and 5% CO₂ in a humidified incubator to a density of 2×10⁵ cells/ml in an 8 chamber slide (Lab-Tek). After replacing the regular DMEM with Optimem, the cells are co-transfected with 10 μg of plasmid pAURNeo(⁻)FlAsH and 5 μg of modified single-stranded oligonucleotide (3S/25G) that is previously complexed with 10 μg lipofectamine, according to the manufacturer's directions (Life Technologies). The cells are treated with the liposome-DNA-oligo mix for 6 hrs at 37° C. Treated cells are washed with PBS and fresh DMEM is added. After a 16-18 hr recovery period, the culture is assayed for gene repair. The same oligonucleotide used in the cell-free extract experiments is used to target transfected plasmid bearing the kan^(s) gene. Correction of the point mutation in this gene eliminates a stop codon and restores full expression. This expression can be detected by adding a small non-fluorescent ligand that bound to a C-C-R-E-C-C (SEQ ID NO:4385) sequence in the genetically modified carboxy terminus of the kan protein, to produce a highly fluorescent complex (FIAsH system, Aurora Biosciences Corporation). Following a 60 min incubation at room temperature with the ligand (FlAsH-EDT2), cells expressing full length kan product acquire an intense green fluorescence detectable by fluorescence microscopy using a fluorescein filter set. Similar experiments are performed using the HygeGFP target as described in Example 2 with a variety of mammalian cells, including, for example, COS-1 and COS-7 cells (African green monkey), and CHO-K1 cells (Chinese hamster ovary). The experiments are also performed with PG12 cells (rat pheocliromocytoma) and ES cells (human embryonic stem cells).

Summary of experimental results. Tables 1, 2 and 3 respectively provide data on the efficiency of gene repair directed by single-stranded oligonucleotides. Table 1 presents data using a cell-free extract from human liver cells (HUH7) to catalyze repair of the point mutation in plasmid pkan^(s)m4021 (see FIG. 1). Table 2 illustrates that the oligomers are not dependent on MSH2 or MSH3 for optimal gene repair activity. Table 3 illustrates data from the repair of a frameshift mutation (FIG. 3) in the tet gene contained in plasmid pTetΔ208. Table 4 illustrates data from repair of the pkan^(s)m4021 point mutation catalyzed by plant cell extracts prepared from canola and musa (banana). Colony numbers are presented as kan^(r) or te^(t) and fold increases (single strand versus double hairpin) are presented for kan^(r) in Table 1.

FIG. 5A is a confocal picture of HeLa cells expressing the corrected fusion protein from an episomal target. Gene repair is accomplished by the action of a modified single-stranded oligonucleotide containing 3 phosphorothioate linkages at each end (3S/25G). FIG. 5B represents a “Z-series” of HeLa cells bearing the corrected fusion gene. This series sections the cells from bottom to top and illustrates that the fluorescent signal is “inside the cells”.

Results. In summary, we have designed a novel class of single-stranded oligonucleotides with backbone modifications at the termini and demonstrate gene repair/conversion activity in mammalian and plant cell-free extracts. We confirm that the all DNA strand of the RNA-DNA double-stranded double hairpin chimera is the active component in the process of gene repair. In some cases, the relative frequency of repair by the novel oligonucleotides of the invention is elevated approximately 3-4-fold when compared to frequencies directed by chimeric RNA-DNA double hairpin oligonucleotides.

This strategy centers around the use of extracts from various sources to correct a mutation in a plasmid using a modified single-stranded or a chimeric RNA-DNA double hairpin oligonucleotide. A mutation is placed inside the coding region of a gene conferring antibiotic resistance in bacteria, here kanamycin or tetracycline. The appearance of resistance is measured by genetic readout in E.coli grown in the presence of the specified antibiotic. The importance of this system is that both phenotypic alteration and genetic inheritance can be measured. Plasmid pK^(s)m4021 contains a mutation (T→G) at residue 4021 rendering it unable to confer antibiotic resistance in E.coli. This point mutation is targeted for repair by oligonucleotides designed to restore kanamycin resistance. To avoid concerns of plasmid contamination skewing the colony counts, the directed correction is from G→C rather than G→T (wild-type). After isolation, the plasmid is electroporated into the DH10B strain of E.coli, which contains inactive RecA protein. The number of kanamycin colonies is counted and normalized by ascertaining the number of ampicillin colonies, a process that controls for the influence of electroporation. The number of colonies generated from three to five independent reactions was averaged and is presented for each experiment. A fold increase number is recorded to aid in comparison.

The original RNA-DNA double hairpin chimera design, e.g., as disclosed in U.S. Pat. No. 5,565,350, consists of two hybridized regions of a single-stranded oligonucleotide folded into a double hairpin configuration. The double-stranded targeting region is made up of a 5 base pair DNA/DNA segment bracketed by 10 base pair RNA/DNA segments. The central base pair is mismatched to the corresponding base pair in the target gene. When a molecule of this design is used to correct the kan^(s) mutation, gene repair is observed (I in FIG. 1A). Chimera II (FIG. 1B) differs partly from chimera I in that only the DNA strand of the double hairpin is mismatched to the target sequence. When this chimera was used to correct the kan^(s) mutation, it was twice as active. In the same study, repair function could be further increased by making the targeting region of the chimera a continuous RNA/DNA hybrid.

Frame shift mutations are repaired. By using plasmid pT^(s)Δ208, described in FIG. 1(C) and FIG. 3, the capacity of the modified single-stranded molecules that showed activity in correcting a point mutation, can be tested for repair of a frameshift. To determine efficiency of correction of the mutation, a chimeric oligonucleotide (Tet I), which is designed to insert a T residue at position 208, is used. A modified single-stranded oligonucleotide (Tet IX) directs the insertion of a T residue at this same site. FIG. 3 illustrates the plasmid and target bases designated for change in the experiments. When all reaction components are present (extract, plasmid, oligomer), tetracycline resistant colonies appear. The colony count increases with the amount of oligonucleotide used up to a point beyond which the count falls off (Table 3). No colonies above background are observed in the absence of either extract or oligonucleotide, nor when a modified single-stranded molecule bearing perfect complementarity is used. FIG. 3 represents the sequence surrounding the target site and shows that a T residue is inserted at the correct site. We have isolated plasmids from fifteen colonies obtained in three independent experiments and each analyzed sequence revealed the same precise nucleotide insertion. These data suggest that the single-stranded molecules used initially for point mutation correction can also repair nucleotide deletions.

Comparison of phosphorothioate oligonucleotides to 2′-O-methyl substituted oligonucleotides. From a comparison of molecules VII and XI, it is apparent that gene repair is more subject to inhibition by RNA residues than by phosphorothioate linkages. Thus, even though both of these oligonucleotides contain an equal number of modifications to impart nuclease resistance, XI (with 16 phosphorothioate linkages) has good gene repair activity while VII (with 16 2′-O-methyl RNA residues) is inactive. Hence, the original chimeric double hairpin oligonucleotide enabled correction directed, in large part, by the strand containing a large region of contiguous DNA residues.

Oligonucleotides can target multiple nucleotide alterations within the same template. The ability of individual single-stranded oligonucleotides to correct multiple mutations in a single target template is tested using the plasmid pK^(s)m4021 and the following single-stranded oligonucleotides modified with 3 phosphorothioate linkages at each end (indicated as underlined nucleotides): Oligo1 is a 25-mer with the sequence TTCGATAAGCCTATGCTGACCCGTG (SEQ ID NO:4377) corrects the original mutation present in the kanamycin resistance gene of pK^(S)m4021 as well as directing another alteration 2 basepairs away in the target sequence (both indicated in boldface); Oligo2 is a 70-mer with the 5′-end sequence TTCGGCTACGACTGGGCACAACAGACAATTGGC (SEQ ID NO:4378) with the remaining nucleotides being completely complementary to the kanamycin resistance gene and also ending in 3 phosphorothioate linkages at the 3′ end. Oligo2 directs correction of the mutation in pK^(s)m4021 as well as directing another alteration 21 basepairs away in the target sequence (both indicated in boldface).

We also use additional oligonucleotides to assay the ability of individual oligonucleotides to correct multiple mutations in the pK^(s)M4021 plasmid. These include, for example, a second 25-mer that alters two nucleotides that are three nucleotides apart with the sequence 5′-TTGTGCCCAGTCGTATCCGAATAGC-3′ (SEQ ID NO:4379); a 70-mer that alters two nucleotides that are 21 nucleotides apart with the sequence 5′-CATCAGAGCAGCCAATTGTCTGTTGTGCCCAGTCGTAGCCGAATAGCCTCTCCACCCAAGCGGCCGGAGA-3′ (SEQ ID NO:4380); and another 70-mer that alters two nucleotides that are 21 nucleotides apart with the sequence 5′-GCTGACAGCCGGAACACGGCGGCATCAGAGCAGCCAATTGTCTGTTGTGCCCAGTCGTAGCCGAATAGCCT-3′ (SEQ ID NO:4381). The nucleotides in the oligonucleotides that direct alteration of the target sequence are underlined and in boldface. These oligonucleotides are modified in the same way as the other oligonucleotides of the invention.

We assay correction of the original mutation in pK^(s)m4021 by monitoring kanamycin resistance (the second alterations which are directed by Oligo2 and Oligo3 are silent with respect to the kanamycin resistance phenotype). In addition, in experiments with Oligo2, we also monitor cleavage of the resulting plasmids using the restriction enzyme Tsp509I which cuts at a specific site present only when the second alteration has occurred (at ATT in Oligo2). We then sequence these clones to determine whether the additional, silent alteration has also been introduced. The results of an analysis are presented below:

Oligo1 (25-mer) Oligo2 (70-mer) Clones with both sites changed 9 7 Clones with a single site changed 0 2 Clones that were not changed 4 1

Nuclease sensitivity of unmodified DNA oligonucleotide. Electrophoretic analysis of nucleic acid recovered from the cell-free extract reactions conducted here confirm that the unmodified single-stranded 25-mer did not survive incubation whereas greater than 90% of the terminally modified oligos did survive (as judged by photo-image analyses of agarose gels).

Plant extracts direct repair. The modified single-stranded constructs can be tested in plant cell extracts. We have observed gene alteration using extracts from multiple plant sources, including, for example, Arabidopsis, tobacco, banana, maize, soybean, canola, wheat, spinach as well as spinach chloroplast extract. We prepare the extracts by grinding plant tissue or cultured cells under liquid nitrogen with a mortar and pestle. We extract 3 ml of the ground plant tissue with 1.5 ml of extraction buffer (20 mM HEPES, pH7.5; 5 mM Kcl; 1.5 mM MgCl₂; 10 mM DTT; 10% [v/v] glycerol; and 1% [w/v] PVP). We then homogenize the samples with 15 strokes of a Dounce homogenizer. Following homogenization, we incubate the samples on ice for 1 hour and centrifuge at 3000×g for 5 minutes to remove plant cell debris. We then determine the protein concentration in the supernatants (extracts) by Bradford assay. We dispense 100 μg (protein) aliquots of the extracts which we freeze in a dry ice-ethanol bath and store at −80° C.

We describe experiments using two sources here: a dicot (canola) and a monocot (banana, Musa acuminata cv. Rasthali). Each vector directs gene repair of the kanamycin mutation (Table 4); however, the level of correction is elevated 2-3 fold relative to the frequency observed with the chimeric oligonucleotide. These results are similar to those observed in the mammalian system wherein a significant improvement in gene repair occurred when modified single-stranded molecules were used.

Tables are attached hereto.

TABLE I Gene repair activity is directed by single-stranded oligonucleotides. Oligonucleotide Plasmid Extract (ug) kan^(r) colonies Fold increase I pK^(S)m4021 10 300 I ↓ 20 418  1.0 × II ↓ 10 537 II ↓ 20 748  1.78 × III ↓ 10 3 III ↓ 20 5  0.01 × IV ↓ 10 112 IV ↓ 20 96  0.22 × V ↓ 10 217 V ↓ 20 342  0.81 × VI ↓ 10 6 VI ↓ 20 39 0.093 × VII ↓ 10 0 VII ↓ 20 0    0 × VIII ↓ 10 3 VIII ↓ 20 5  0.01 × IX ↓ 10 936 IX ↓ 20 1295  3.09 × X ↓ 10 1140 X ↓ 20 1588  3.7 × XI ↓ 10 480 XI ↓ 20 681  1.6 × XII ↓ 10 18 XII ↓ 20 25 0.059 × XIII ↓ 10 0 XIII ↓ 20 4 0.009 × — ↓ 20 0 I ↓ — 0 Plasmid pK^(s)m4021 (1 μg), the indicated oligonucleotide (1.5 μg chimeric oligonucleotide or 0.55 μg single-stranded oligonucleotide; molar ratio of oligo to plasmid of 360 to 1) and either 10 or 20 μg of HUH7 cell-free extract were incubated 45 min at 37° C. Isolated plasmid DNA was electroporated into E. coli (strain DH10B) and the number of kan^(r) colonies counted. The data represent the number of kanamycin resistant colonies per 10⁶ ampicillin resistant colonies generated from the same reaction and is the average of three experiments (standard deviation usually less than +/−15%). Fold increase is defined relative to 418 kan^(r) colonies (second reaction) and in all reactions was calculated using the 20 μg sample.

TABLE II Modified single-stranded oligomers are not dependent on MSH2 or MSH3 for optimal gene repair activity. A. Oligonucleotide Plasmid Extract kan^(r) colonies IX (3S/25G) ↓ HUH7 637 X (6S/25G) ↓ HUH7 836 IX ↓ MEF2^(−/−) 781 X ↓ MEF2^(−/−) 676 IX ↓ MEF3^(−/−) 582 X ↓ MEF3^(−/−) 530 IX ↓ MEF^(+/+) 332 X ↓ MEF^(+/+) 497 — ↓ MEF2^(−/−) 10 — ↓ MEF3^(−/−) 5 — ↓ MEF^(+/+) 14 Chimeric oligonucleotide (1.5 μg) or modified single-stranded oligonucleotide (0.55 μg) was incubated with 1 μg of plasmid pK^(s)m4021 and 20 μg of the indicated extracts. MEF represents mouse embryonic fibroblasts with either MSH2 (2^(−/−)) or MSH3 (3^(−/−)) deleted. MEF^(+/+) indicates wild-type mouse embryonic fibroblasts. The other reaction components were then added and processed through the bacterial readout system. The data represent the number of kanamycin resistant colonies per 10⁶ ampicillin resistant colonies.

TABLE III Frameshift mutation repair is directed by single-stranded oligonucleotides Oligonucleotide Plasmid Extract tet^(r) colonies Tet IX (3S/25A; 0.5 μg) pT^(S)Δ208 (1 μg) — 0 — ↓ 20 μg 0 Tet IX (0.5 μg) ↓ ↓ 48 Tet IX (1.5 μg) ↓ ↓ 130 Tet IX (2.0 μg) ↓ ↓ 68 Tet I (chimera; 1.5 μg) ↓ ↓ 48 Each reaction mixture contained the indicated amounts of plasmid and oligonucleotide. The extract used for these experiments came from HUH7 cells. The data represent the number of tetracycline resistant colonies per 10⁶ ampicillin resistant colonies generated from the same reaction and is the average of 3 independent experiments. Tet I is a chimeric oligonucleotide and Tet IX is a modified single-stranded oligonucleotide that are designed to insert a T residue at position 208 of pT^(s)Δ208. These oligonucleotides are equivalent to structures I and IX in FIG. 2.

TABLE IV Plant cell-free extracts support gene repair by single-stranded oligonucleotides Oligonucleotide Plasmid Extract kan^(r) colonies II (chimera) pK^(S)m402l 30 μg Canola 337 IX (3S/25G) ↓ Canola 763 X (6S/25G) ↓ Canola 882 II ↓ Musa 203 IX ↓ Musa 343 X ↓ Musa 746 — ↓ Canola 0 — ↓ Musa 0 IX ↓ — Canola 0 X ↓ — Musa 0 Canola or Musa cell-free extracts were tested for gene repair activity on the kanamycin-sensitive gene as previously described in (18). Chimeric oligonucleotide II (1.5 μg) and modified single-stranded oligonucleotides IX and X (0.55 μg) were used to correct pK^(S)m4021. Total number of kan^(r) colonies are present per 10⁷ ampicillin resistant colonies and represent an average of four independent experiments.

TABLE V Gene repair activity in cell-free extracts prepared from yeast (Saccharomyces cerevisiae) Cell-type Plasmid Chimeric Oligo SS Oligo kan^(r)/amp^(r) × 10⁶ Wild type pKan^(s)m4021 1 μg 0.36 Wild type ↓ 1 μg 0.81 ΔRAD52 ↓ 1 μg 10.72 ΔRAD52 ↓ 1 μg 17.41 ΔPMS1 ↓ 1 μg 2.02 ΔPMS1 ↓ 1 μg 3.23 In this experiment, the kan^(s) gene in pKan^(s)4021 is corrected by either a chimeric double-hairpin oligonucleotide or a single-stranded oligonucleotide containing three thioate linkages at each end (3S/25G).

EXAMPLE 2 Yeast Cell Targeting Assay Method for Base Alteration and Preferred Oligonucleotide Selection

In this example, single-stranded oligonucleotides with modified backbones and double-hairpin oligonucleotides with chimeric, RNA-DNA backbones are used to measure gene repair using two episomal targets with a fusion between a hygromycin resistance gene and eGFP as a target for gene repair. These plasmids are pAURHYG(rep)GFP, which contains a point mutation in the hygromycin resistance gene (FIG. 7), pAURHYG(ins)GFP, which contains a single-base insertion in the hygromycin resistance gene (FIG. 7) and pAURHYG(Δ)GFP which has a single base deletion. We also use the plasmid containing a wild-type copy of the hygromycin-eGFP fusion gene, designated pAURHYG(wt)GFP, as a control. These plasmids also contain an aureobasidinA resistance gene. In pAURHYG(rep)GFP, hygromycin resistance gene function and green fluorescence from the eGFP protein are restored when a G at position 137, at codon 46 of the hygromycin B coding sequence, is converted to a C thus removing a premature stop codon in the hygromycin resistance gene coding region. In pAURHYG(ins)GFP, hygromycin resistance gene function and green fluorescence from the eGFP protein are restored when an A inserted between nucleotide positions 136 and 137, at codon 46 of the hygromycin B coding sequence, is deleted and a C is substituted for the T at position 137, thus correcting a frameshift mutation and restoring the reading frame of the hygromycin-eGFP fusion gene.

We synthesize the set of three yeast expression constructs pAURHYG(rep)eGFP, pAURHYG(Δ)eGFP, pAURHYG(ins)eGFP, that contain a point mutation at nucleotide 137 of the hygromycin-B coding sequence as follows. (rep) indicates a T137→G replacement, (Δ) represents a deletion of the G137 and (ins) represents an A insertion between nucleotides 136 and 137. We construct this set of plasmids by excising the respective expression cassettes by restriction digest from pHyg(x)EGFP and ligation into pAUR123 (Panvera, Calif.). We digest 10 μg pAUR123 vector DNA, as well as, 10 μg of each pHyg(x)EGFP construct with KpnI and SaII (NEB). We gel purify each of the DNA fragments and prepare them for enzymatic ligation. We ligate each mutated insert into pHygEGFP vector at 3:1 molar ration using T4 DNA ligase (Roche). We screen clones by restriction digest, confirm by Sanger dideoxy chain termination sequencing and purify using a Qiagen maxiprep kit.

We use this system to assay the ability of five oligonucleotides (shown in FIG. 8) to support correction under a variety of conditions. The oligonucleotides which direct correction of the mutation in pAURHYG(rep)GFP can also direct correction of the mutation in pAURHYG(ins)GFP. Three of the four oligonucleotides (HygE3T/25, HygE3T/74 and HygGG/Rev) share the same 25-base sequence surrounding the base targeted for alteration. HygGG/Rev is an RNA-DNA chimeric double hairpin oligonucleotide of the type described in the prior art. One of these oligonucleotides, HygE3T/74, is a 74-base oligonucleotide with the 25-base sequence centrally positioned. The fourth oligonucleotide, designated HygE3T/74α, is the reverse complement of HygE3T/74. The fifth oligonucleotide, designated Kan70T, is a non-specific, control oligonucleotide which is not complementary to the target sequence. Alternatively, an oligonucleotide of identical sequence but lacking a mismatch to the target or a completely thioate modified oligonucleotide or a completely 2-O-methylated modified oligonucleotide may be used as a control.

Oligonucleotide synthesis and cells. We synthesized and purified the chimeric, double-hairpin oligonucleotides and single-stranded oligonucleotides (including those with the indicated modifications) as described in Example 1. Plasmids used for assay were maintained stably in yeast (Saccharomyces cerevisiae) strain LSY678 MATα at low copy number under aureobasidin selection. Plasmids and oligonucleotides are introduced into yeast cells by electroporation as follows: to prepare electrocompetent yeast cells, we inoculate 10 ml of YPD media from a single colony and grow the cultures overnight with shaking at 300 rpm at 30° C. We then add 30 ml of fresh YPD media to the overnight cultures and continue shaking at 30° C. until the OD₆₀₀ was between 0.5 and 1.0 (3-5 hours). We then wash the cells by centrifuging at 4° C. at 3000 rpm for 5 minutes and twice resuspending the cells in 25 ml ice-cold distilled water. We then centrifuge at 4° C. at 3000 rpm for 5 minutes and resuspend in 1 ml ice-cold 1M sorbitol and then finally centrifuge the cells at 4° C. at 5000 rpm for 5 minutes and resuspend the cells in 120 μl 1M sorbitol. To transform electrocompetent cells with plasmids or oligonucleotides, we mix 40 μl of cells with 5 μg of nucleic acid, unless otherwise stated, and incubate on ice for 5 minutes. We then transfer the mixture to a 0.2 cm electroporation cuvette and electroporate with a BIO-RAD Gene Pulser apparatus at 1.5 kV, 25 μF, 200Ω for one five-second pulse. We then immediately resuspend the cells in 1 ml YPD supplemented with 1M sorbitol and incubate the cultures at 30° C. with shaking at 300 rpm for 6 hours. We then spread 200 μl of this culture on selective plates containing 300 μg/ml hygromycin and spread 200 μl of a 10⁵ dilution of this culture on selective plates containing 500 ng/ml aureobasidinA and/or and incubate at 30° C. for 3 days to allow individual yeast colonies to grow. We then count the colonies on the plates and calculate the gene conversion efficiency by determining the number of hygromycin resistance colonies per 10⁵ aureobasidinA resistant colonies.

Frameshift mutations are repaired in yeast cells. We test the ability of the oligonucleotides shown in FIG. 8 to correct a frameshift mutation in vivo using LSY678 yeast cells containing the plasmid pAURHYG(ins)GFP. These experiments, presented in Table 6, indicate that these oligonucleotides can support gene correction in yeast cells. These data reinforce the results described in Example 1 indicating that oligonucleotides comprising phosphorothioate linkages facilitate gene correction much more efficiently than control duplex, chimeric RNA-DNA oligonucleotides. This gene correction activity is also specific as transformation of cells with the control oligonucleotide Kan70T produced no hygromycin resistant colonies above background and thus Kan70T did not support gene correction in this system. In addition, we observe that the 74-base oligonucleotide (HygE3T/74) corrects the mutation in pAURHYG(ins)GFP approximately five-fold more efficiently than the 25-base oligonucleotide (HygE3T/25). We also perform control experiments with LSY678 yeast cells containing the plasmid pAURHYG(wt)GFP. With this strain we observed that even without added oligonucleotides, there are too many hygromycin resistant colonies to count.

We also use additional oligonucleotides to assay the ability of individual oligonucleotides to correct multiple mutations in the pAUIRHYG(x)eGFP plasmid. These include, for example, one that alters two basepairs that are 3 nucleotides apart is a 74-mer with the sequence 5′-CTCGTGCTTTCAGCTTCGATGTAGGAGGGCGTGGGTACGTCCTGCGGGTAAATAGCTGCGCCGATGGTTTCTAC-3′ (SEQ ID NO:4382); a 74-mer that alters two basepairs that are 15 nucleotides apart with the sequence 5′-CTCGTGCTTTCAGCTTCGATGTAGGAGGGCGTGGATACGTCCTGCGGGTAAACAGCTGCGCCGATGGTTTCTAC-3 (SEQ ID NO:4383)′; and a 74-mer that alters two basepairs that are 27 nucleotides apart with the sequence 5′-CTCGTGCTTTCAGCTTCGATGTAGGAGGGCGTGGATACGTCCTGCGGGTAAATAGCTGCGCCGACGGTTTCTAC (SEQ ID NO:4384). The nucleotides in these oligonucleotides that direct alteration of the target sequence are underlined and in boldface. These oligonucleotides are modified in the same ways as the other oligonucleotides of the invention.

Oligonucleotides targeting the sense strand direct gene coffection more efficiently. We compare the ability of single-stranded oligonucleotides to target each of the two strands of the target sequence of both pAURHYG(ins)GFP and pAURHYG(rep)GFP. These experiments, presented in Tables 7 and 8, indicate that an oligonucleotide, HygE3T/74α, with sequence complementary to the sense strand (i.e. the strand of the target sequence that is identical to the mRNA) of the target sequence facilitates gene correction approximately ten-fold more efficiently than an oligonucleotide, HygE3T/74, with sequence complementary to the non-transcribed strand which serves as the template for the synthesis of RNA. As indicated in Table 7, this effect was observed over a range of oligonucleotide concentrations from 0-3.6 μg, although we did observe some variability in the difference between the two oligonucleotides (indicated in Table 7 as a fold difference between HygE3T/74α and HygE3T/74). Furthermore, as shown in Table 8, we observe increased efficiency of correction by HygE3T/74α relative to HygE3T/74 regardless of whether the oligonucleotides were used to correct the base substitution mutation in pAURHYG(rep)GFP or the insertion mutation in pAURHYG(ins)GFP. The data presented in Table 8 further indicate that the single-stranded oligonucleotides correct a base substitution mutation more efficiently than an insertion mutation. However, this last effect was much less pronounced and the oligonucleotides of the invention are clearly able efficiently to correct both types of mutations in yeast cells. In addition, the role of transcription is investigated using plasmids with inducible promoters such as that described in FIG. 10.

Optimization of oligonucleotide concentration. To determine the optimal concentration of oligonucleotide for the purpose of gene alteration, we test the ability of increasing concentrations of Hyg3T/74α to correct the mutation in pAURHYG(rep)GFP contained in yeast LSY678. We chose this assay system because our previous experiments indicated that it supports the highest level of correction. However, this same approach could be used to determine the optimal concentration of any given oligonucleotide. We test the ability of Hyg3T/74α to correct the mutation in pAURHYG(rep)GFP contained in yeast LSY678 over a range of oligonucleotide concentrations from 0-10.0 μg. As shown in Table 9, we observe that the correction efficiency initially increases with increasing oligonucleotide concentration, but then declines at the highest concentration tested.

Tables are attached hereto.

TABLE 6 Correction of an insertion mutation in pAURHYG(ins)GFP by HygGG/Rev, HygE3T/25 and HygE3T/74 Colonies on Colonies on Correction Oligonucleotide Tested Hygromycin Aureobasidin (/10⁵) Efficiency HygGG/Rev 3 157 0.02 HygE3T/25 64 147 0.44 HygE3T/74 280 174 1.61 Kan70T 0 — —

TABLE 7 An oligonucleotide targeting the sense strand of the target sequence corrects more efficiently. Colonies per hygromycin plate Amount of Oligonucleotide (μg) HygE3T/74 HygE3T/74α 0 0 0 0.6 24 128 (8.4x)* 1.2 69 140 (7.5x)* 2.4 62 167 (3.8x)* 3.6 29 367 (15x)* *The numbers in parentheses represent the fold increase in efficiency for targeting the non-transcribed strand as compared to the other strand of a DNA duplex that encodes a protein.

TABLE 8 Correction of a base substitution mutation is more efficient than correction of a frame shift mutation. Oligonucleotide Plasmid tested (contained in LSY678) Tested (5 μg) pAURHYG(ins)GFP pAURHYG(rep)GFP HygE3T/74 72 277 HygE3T/74α 1464 2248 Kan70T 0 0

TABLE 9 Optimization of oligonucleotide concentration in electroporated yeast cells. Colonies on Colonies on Amount (μg) hygromycin aureobasidin (/10⁵) Correction efficiency 0 0 67 0 1.0 5 64 0.08 2.5 47 30 1.57 5.0 199 33 6.08 7.5 383 39 9.79 10.0 191 33 5.79

EXAMPLE 3 Cultured Cell Manipulation

Mononuclear cells are isolated from human umbilical cord blood of normal donors using Ficoll Hypaque (Pharmacia Biotech, Uppsala, Sweden) density centrifugation. CD34+ cells are immunomagnetically purified from mononuclear cells using either the progenitor or Multisort Kits (Miltenyi Biotec, Auburn, Calif.). Lin⁻CD38⁻ cells are purified from the mononuclear cells using negative selection with StemSep system according to the manufacturer's protocol (Stem Cell Technologies, Vancouver, Calif.). Cells used for microinjecton are either freshly isolated or cryopreserved and cultured in Stem Medium (S Medium) for 2 to 5 days prior to microinjecton. S Medium contains Iscoves' Modified Dulbecco's Medium without phenol red (IMDM) with 100 μg/ml glutamine/penicillin/streptomycin, 50 mg/ml bovine serum albumin, 50 μg/ml bovine pancreatic insulin, 1 mg/ml human transferrin, and IMDM; Stem Cell Technologies), 40 μg/ml low-density lipoprotein (LDL; Sigma, St. Louis, Mo.), 50 mM HEPEs buffer and 50 μM 2-mercaptoethanol, 20 ng/ml each of thrombopoietin, flt-3 ligand, stem cell factor and human IL-6 (Pepro Tech Inc., Rocky Hill, N.J.). After microinjection, cells are detached and transferred in bulk into wells of 48 well plates for culturing.

35 mm dishes are coated overnight at 40° C. with 50 μg/ml Fibronectn (FN) fragment CH-296 (Retronectn; TaKaRa Biomedicals, Panvera, Madison, Wis.) in phosphate buffered saline and washed with IMDM containing glutamine/penicillin/streptomycin. 300 to 2000 cells are added to cloning rings and attached to the plates for 45 minutes at 37° C. prior to microinjecton. After incubation, cloning rings are removed and 2 ml of S Medium are added to each dish for microinjecton. Pulled injection needles with a range of 0.22μ to 0.3μ outer tip diameter are used. Cells are visualized with a microscope equipped with a temperature controlled stage set at 37° C. and injected using an electronically interfaced Eppendorf Micromanipulator and Transjector. Successfully injected cells are intact, alive and remain attached to the plate post injection. Molecules that are flourescently labeled allow determination of the amount of oligonucleotide delivered to the cells.

For in vitro erythropoiesis from Lin⁻CD38⁻ cells, the procedure of Malik, 1998 can be used. Cells are cultured in ME Medium for 4 days and then cultured in E Medium for 3 weeks. Erythropoiesis is evident by glycophorin A expression as well as the presence of red color representing the presence of hemoglobin in the cultured cells. The injected cells are able to retain their proliferative capacity and the ability to generate myeloid and erythoid progeny. CD34+ cells can convert a normal A (β^(A)) to sickle T (β^(S)) mutation in the β-globin gene or can be altered using any of the oligonucleotides of the invention herein for correction or alteration of a normal gene to a mutant gene. Alternatively, stem cells can be isolated from blood of humans having genetic disease mutations and the oligonucleotides of the invention can be used to correct a defect or to modify genomes within those cells.

Alternatively, non-stem cell populations of cultured cells can be manipulated using any method known to those of skill in the art including, for example, the use of polycations, cationic lipids, liposomes, polyethylenimine (PEI), electroporaton, biolistcs, calcium phophate precipitation, or any other method known in the art.

Notes on the Tables Presented Below:

Each of the following tables presents, for the specified human gene, a plurality of mutations that are known to confer a clinically-relevant phenotype and, for each mutation, the oligonucleotides that can be used to correct the respective mutation site-specifically in the human genome according to the present invention.

The left-most column identifies each mutation and the clinical phenotype that the mutation confers.

For most entries, the mutation is identified at both the nucleic acid and protein level. At the amino acid level, mutations are presented according to the following standard nomenclature. The centered number identifies the position of the mutated codon in the protein sequence; to the left of the number is the wild type residue and to the right of the number is the mutant codon. Codon numbering is according to the Human Gene Mutation Database, Cardiff, Wales, UK. Terminator codons are shown as “TERM”. At the nucleic acid level, the entire triplet of the wild type and mutated codons is shown.

The middle column presents, for each mutation, four oligonucleotides capable of repairing the mutation site-specifically in the human genome or in cloned human DNA including human DNA in artificial chromosomes, episomes, plasmids, or other types of vectors. The oligonucleotides of the invention, however, may include any of the oligonucleotides sharing portions of the sequence of the 121 base sequence. Thus, oligonucleotides of the invention for each of the depicted targets may be 18, 19, 20 up to about 121 nucleotides in length. Sequence may be added non-symmetrically.

All oligonucleotides are presented, per convention, in the 5′ to 3′ orientation. The nucleotide that effects the change in the genome is underlined and presented in bold.

The first of the four oligonucleotides for each mutation is a 121 nt oligonucleotide centered about the repair nucleotide. The second oligonucleotide, its reverse complement, targets the opposite strand of the DNA duplex for repair. The third oligonucleotide is the minimal 17 nt domain of the first oligonucleotide, also centered about the repair nucleotide. The fourth oligonucleotide is the reverse complement of the third, and thus represents the minimal 17 nt domain of the second.

The third column of each table presents the SEQ ID NO: of the respective repair oligonucleotide.

EXAMPLE 4 Adenosine Deaminase (ADA)

Adenosine deaminase (ADA, EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine or 2′-deoxyinosine respectively. ADA deficiency has been identified as the metabolic basis for 20-30% of cases with recessively inherited severe combined immunodeficiency (SCID). Affected infants are subject to recurrent chronic viral, fungal, protozoal, and bacterial infections and frequently present with persistent diarrhea, failure to thrive and candidiasis. In patients homozygous for ADA deficiency, 2′-deoxyadenosine accumulating during the rapid turnover of cells rich in DNA is converted back to dATP, either by adenosine kinase or deoxycytidine kinase. Many hypotheses have been advanced to explain the specific toxicity to the immune system in ADA deficiency. The apparently selective accumulation of dATP in thymocytes and peripheral blood B cells, with resultant inhibition of ribonucleotide reductase and DNA synthesis is probably the principal mechanism.

The structural gene for ADA is encoded as a single 32 kb locus containing 12 exons. Studies of the molecular defect in ADA-deficient patients have shown that mRNA is usually detectable in normal or supranormal amounts. Specific base substitution mutations have been detected in the majority of cases with the complete deficiency. A C-to-T base substitution mutation in exon 11 accounts for a high proportion of these, whilst a few patents are homozygous for large deletions encompassing exon I. A common point mutation resulting in a heat-labile ADA has been characterised in some patients with partial ADA deficiency, a disorder with an apparently increased prevalence in the Caribbean.

As yet no totally effective therapy for ADA deficiency has been reported, except in those few cases where bone marrow from an HLA/MLR compatible sibling donor was available.

Two therapeutic approaches have provided long-term benefit in specific instances. First, reconstitution using T cell depleted mismatched sibling marrow has been encouraging, particularly in early presenters completely deficient in ADA. Secondly, therapy with polyethylene glycol-modified adenosine deaminase (PEG-ADA) for more than 5 years has produced a sustained increase in lymphocyte numbers and mitogen responses together with evidence of in vivo B cell function. Success has generally been achieved in late presenters with residual ADA activity in mononuclear cells.

ADA deficiency has been chosen as the candidate disease for gene replacement therapy and the first human experiment commenced in 1990. The clinical consequences of overexpression of ADA activity—one of the potential hazards of gene implant—are known and take the form of an hereditary haemolytic anaemia associated with a tissue-specific increase in ADA activity. The genetic basis for the latter autosomal dominant disorder seemingly relates to markedly increased levels of structurally normal ADA mRNA.

TABLE 10 ADA Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Adenosine deaminase AGAGACCCACCGAGCGGCGGCGGAGGGAGCAGCGCCGGGG 1 deficiency CGCACGAGGGCACCATGGCC C AGACGCCCGCCTTCGACAAG GLN3TERM CCCAAAGTGAGCGCGCGCGGGGGCTCCGGGGACGGGGGTC CAG to TAG GACCCCCGTCCCCGGAGCCCCCGCGCGCGCTCACTTTGGG 2 CTTGTCGAAGGCGGGCGTCT G GGCCATGGTGCCCTCGTGCG CCCCGGCGCTGCTCCCTCCGCCGCCGCTCGGTGGGTCTCT CCATGGCC C AGACGCCC 3 GGGCGTCT G GGCCATGG 4 Adenosine deaminase TATTTGTTCTCTCTCTCCCTTTCTCTCTCTCTTCCCCCTGCCC 5 deficiency CCTTGCAGGTAGAACTG C ATGTCCACCTAGACGGATCCATCA HIS15ASP AGCCTGAAACCATCTTATACTATGGCAGGTAAGTCC CAT to GAT GGACTTACCTGCCATAGTATAAGATGGTTTCAGGCTTGATGGA 6 TCCGTCTAGGTGGACAT G CAGTTCTACCTGCAAGGGGGCAG GGGGAAGAGAGAGAGAAAGGGAGAGAGAGAACAAATA TAGAACTG C ATGTCCAC 7 GTGGACAT G CAGTTCTA 8 Adenosine deaminase TCCCTTTCTCTCTCTCTTCCCCCTGCCCCCTTGCAGGTAGAA 9 deficiency CTGCATGTCCACCTAGAC G GATCCATCAAGCCTGAAACCATC GLY20ARG TTATACTATGGCAGGTAAGTCCATACAGAAGAGCCCT GGA to AGA AGGGCTCTTCTGTATGGACTTACCTGCCATAGTATAAGATGGT 10 TTCAGGCTTGATGGATC C GTCTAGGTGGACATGCAGTTCTAC CTGCAAGGGGGCAGGGGGAAGAGAGAGAGAAAGGGA ACCTAGAC G GATCCATC 11 GATGGATC C GTCTAGGT 12 Adenosine deaminase CCTGGAGCTCCCAAGGGACTTGGGGAAGGTTGTTCCCAACC 13 deficiency CCTTTCTTCCCTTCCCAGG G GCTGCCGGGAGGCTATCAAAAG GLY74CYS GATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGG GGC to TGC CCTCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCCTTTT 14 GATAGCCTCCCGGCAGC C CCTGGGAAGGGAAGAAAGGGGTT GGGAACAACCTTCCCCAAGTCCCTTGGGAGCTCCAGG CTATCGCG G GCTGCCGG 15 CCGGCAGC C CGCGATAG 16 Adenosine Deaminase GCTCCCAAGGGACTTGGGGAAGGTTGTTCCCAACCCCTTTCT 17 Deficiency TCCCTTCCCAGGGGCTGC C GGGAGGCTATCAAAAGGATCGC ARG76TRP CTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCGTGG CGG to TGG CCACGCCCTCTTTGGCCTTCATCTCTACAAACTCATAGGCGAT 18 CCTTTTGATAGCCTCCC G GCAGCCCCTGGGAAGGGAAGAAA GGGGTTGGGAACAACCTTCCCCAAGTCCCTTGGGAGC GGGGCTGC C GGGAGGCT 19 AGCCTCCC G GCAGCCCC 20 Adenosine Deaminase TTGGGGAAGGTTGTTCCCAACCCCTTTCTTCCCTTCCCAGGG 21 Deficiency GCTGCCGGGAGGCTATCA A AAGGATCGCCTATGAGTTTGTAG LYS80ARG AGATGAAGGCCAAAGAGGGCGTGGTGTATGTGGAGGT AAA to AGA ACCTCCACATACACCACGCCCTCTTTGGCCTTCATCTCTACAA 22 ACTCATAGGCGATCCTT T TGATAGCCTCCCGGCAGCCCCTGG GAAGGGAAGAAAGGGGTTGGGAACAACCTTCCCCAA GGCTATCA A AAGGATCG 23 CGATCCTT T TGATAGCC 24 Adenosine deaminase GTTGTTCCCAACCCCTTTCTTCCCTTCCCAGGGGCTGCCGGG 25 deficiency AGGCTATCAAAAGGATCG C CTATGAGTTTGTAGAGATGAAGG ALA83ASP CCAAAGAGGGCGTGGTGTATGTGGAGGTGCGGTACAG GCC to GAC CTGTACCGCACCTCCACATACACCACGCCCTCTTTGGCCTTC 26 ATCTCTACAAACTCATAG G CGATCCTTTTGATAGCCTCCCGGC AGCCCCTGGGAAGGGAAGAAAGGGGTTGGGAACAAC AAGGATCG C CTATGAGT 27 ACTCATAG G CGATCCTT 28 Adenosine deaminase AGGCTATCAAAAGGATCGCCTATGAGTTTGTAGAGATGAAGG 29 deficiency CCAAAGAGGGCGTGGTGT A TGTGGAGGTGCGGTACAGTCCG TYR97CYS CACCTGCTGGCCAACTCCAAAGTGGAGCCAATCCCCTG TAT to TGT CAGGGGATTGGCTCCACTTTGGAGTTGGCCAGCAGGTGCGG 30 ACTGTACCGCACCTCCACA T ACACCACGCCCTCTTTGGCCTT CATCTCTACAAACTCATAGGCGATCCTTTTGATAGCCT CGTGGTGT A TGTGGAGG 31 CCTCCACA T ACACCACG 32 Adenosine deaminase GGATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCG 33 deficiency TGGTGTATGTGGAGGTGC G GTACAGTCCGCACCTGCTGGCC ARG101GLN AACTCCAAAGTGGAGCCAATCCCCTGGAACCAGGCTGA CGG to CAG TCAGCCTGGTTCCAGGGGATTGGCTCCACTTTGGAGTTGGCC 34 AGCAGGTGCGGACTGTAC C GCACCTCCACATACACCACGCC CTCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCC GGAGGTGC G GTACAGTC 35 GACTGTAC C GCACCTCC 36 Adenosine deaminase GGATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCG 37 deficiency TGGTGTATGTGGAGGTGC G GTACAGTCCGCACCTGCTGGCC ARG101LEU AACTCCAAAGTGGAGCCAATCCCCTGGAACCAGGCTGA CGG to CTG TCAGCCTGGTTCCAGGGGATTGGCTCCACTTTGGAGTTGGCC 38 AGCAGGTGCGGACTGTAC C GCACCTCCACATACACCACGCC CTCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCC GGAGGTGC G GTACAGTC 39 GACTGTAC C GCACCTCC 40 Adenosine deaminase AGGATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGC 41 deficiency GTGGTGTATGTGGAGGTG C GGTACAGTCCGCACCTGCTGGC ARG101TRP CAACTCCAAAGTGGAGCCAATCCCCTGGAACCAGGCTG CGG to TGG CAGCCTGGTTCCAGGGGATTGGCTCCACTTTGGAGTTGGCCA 42 GCAGGTGCGGACTGTACC G CACCTCCACATACACCACGCCC TCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCCT TGGAGGTG C GGTACAGT 43 ACTGTACC G CACCTCCA 44 Adenosine deaminase ATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCGTGGTGTATG 45 deficiency TGGAGGTGCGGTACAGTC C GCACCTGCTGGCCAACTCCAAA PRO104LEU GTGGAGCCAATCCCCTGGAACCAGGCTGAGTGAGTGAT CCG to CTG ATCACTCACTCAGCCTGGTTCCAGGGGATTGGCTCCACTTTG 46 GAGTTGGCCAGCAGGTGC G GACTGTACCGCACCTCCACATA CACCACGCCCTCTTTGGCCTTCATCTCTACAAACTCAT GTACAGTC C GCACCTGC 47 GCAGGTGC G GACTGTAC 48 Adenosine deaminase TTTGTAGAGATGAAGGCCAAAGAGGGCGTGGTGTATGTGGAG 49 deficiency GTGCGGTACAGTCCGCAC C TGCTGGCCAACTCCAAAGTGGA LEU106VAL GCCAATCCCCTGGAACCAGGCTGAGTGAGTGATGGGCC CTG to GTG GGCCCATCACTCACTCAGCCTGGTTCCAGGGGATTGGCTCCA 50 CTTTGGAGTTGGCCAGCA G GTGCGGACTGTACCGCACCTCC ACATACACCACGCCCTCTTTGGCCTTCATCTCTACAAA GTCCGCAC C TGCTGGCC 51 GGCCAGCA G GTGCGGAC 52 Adenosine deaminase TAGAGATGAAGGCCAAAGAGGGCGTGGTGTATGTGGAGGTG 53 deficiency CGGTACAGTCCGCACCTGC T GGCCAACTCCAAAGTGGAGCC LEU107PRO AATCCCCTGGAACCAGGCTGAGTGAGTGATGGGCCTGGA CTG to CCG TCCAGGCCCATCACTCACTCAGCCTGGTTCCAGGGGATTGGC 54 TCCACTTTGGAGTTGGCC A GCAGGTGCGGACTGTACCGCAC CTCCACATACACCACGCCCTCTTTGGCCTTCATCTCTA GCACCTGC T GGCCAACT 55 AGTTGGCC A GCAGGTGC 56 Adenosine deaminase GCCTTCCTTTTGCCTCAGGCCCATCCCTACTCCTCTCCTCAC 57 deficiency ACAGAGGGGACCTCACCC C AGACGAGGTGGTGGCCCTAGTG PRO126GLN GGCCAGGGCCTGCAGGAGGGGGAGCGAGACTTCGGGGT CCA to CAA ACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCCCTGGCCCAC 58 TAGGGCCACCACCTCGTCT G GGGTGAGGTCCCCTCTGTGTG AGGAGAGGAGTAGGGATGGGCCTGAGGCAAAAGGAAGGC CCTCACCC C AGACGAGG 59 CCTCGTCT G GGGTGAGG 60 Adenosine deaminase TTTGCCTCAGGCCCATCCCTACTCCTCTCCTCACACAGAGGG 61 deficiency GACCTCACCCCAGACGAG G TGGTGGCCCTAGTGGGCCAGGG TAL129MET CCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCCC GTG to ATG GGGCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCCC 62 TGGCCCACTAGGGCCACCA C CTCGTCTGGGGTGAGGTCCCC TCTGTGTGAGGAGAGGAGTAGGGATGGGCCTGAGGCAAA CAGACGAG G TGGTGGCC 63 GGCCACCA C CTCGTCTG 64 Adenosine deaminase ACAGAGGGGACCTCACCCCAGACGAGGTGGTGGCCCTAGTG 65 deficiency GGCCAGGGCCTGCAGGAGG G GGAGCGAGACTTCGGGGTCA GLY140GLU AGGCCCGGTCCATCCTGTGCTGCATGCGCCACCAGCCCAG GGG to GAG CTGGGCTGGTGGCGCATGCAGCACAGGATGGACCGGGCCTT 66 GACCCCGAAGTCTCGCTCC C CCTCCTGCAGGCCCTGGCCCA CTAGGGCCACCACCTCGTCTGGGGTGAGGTCCCCTCTGT GCAGGAGG G GGAGCGAG 67 CTCGCTCC C CCTCCTGC 68 Adenosine deaminase GGGACCTCACCCCAGACGAGGTGGTGGCCCTAGTGGGCCAG 69 deficiency GGCCTGCAGGAGGGGGAGC G AGACTTCGGGGTCAAGGCCC ARG142GLN GGTCCATCCTGTGCTGCATGCGCCACCAGCCCAGTGAGTA CGA to CAA TACTCACTGGGCTGGTGGCGCATGCAGCACAGGATGGACCG 70 GGCCTTGACCCCGAAGTCT C GCTCCCCCTCCTGCAGGCCCT GGCCCACTAGGGCCACCACCTCGTCTGGGGTGAGGTCCC GGGGGAGC G AGACTTCG 71 CGAAGTCT C GCTCCCCC 72 Adenosine deaminase GGGGACCTCACCCCAGACGAGGTGGTGGCCCTAGTGGGCCA 73 deficiency GGGCCTGCAGGAGGGGGAG C GAGACTTCGGGGTCAAGGCC ARG142TERM CGGTCCATCCTGTGCTGCATGCGCCACCAGCCCAGTGAGT CGA to TGA ACTCACTGGGCTGGTGGCGCATGCAGCACAGGATGGACCGG 74 GCCTTGACCCCGAAGTCTC G CTCCCCCTCCTGCAGGCCCTG GCCCACTAGGGCCACCACCTCGTCTGGGGTGAGGTCCCC AGGGGGAG C GAGACTTC 75 GAAGTCTC G CTCCCCCT 76 Adenosine deaminase TGGTGGCCCTAGTGGGCCAGGGCCTGCAGGAGGGGGAGCG 77 deficiency AGACTTCGGGGTCAAGGCCC G GTCCATCCTGTGCTGCATGC ARG149GLN GCCACCAGCCCAGTGAGTAGGATCACCGCCCTGCCCAGGG CGG to CAG CCCTGGGCAGGGCGGTGATCCTACTCACTGGGCTGGTGGCG 78 CATGCAGCACAGGATGGAC C GGGCCTTGACCCCGAAGTCTC GCTCCCCCTCCTGCAGGCCCTGGCCCACTAGGGCCACCA CAAGGCCC G GTCCATCC 79 GGATGGAC C GGGCCTTG 80 Adenosine deaminase GTGGTGGCCCTAGTGGGCCAGGGCCTGCAGGAGGGGGAGC 81 deficiency GAGACTTCGGGGTCAAGGCC C GGTCCATCCTGTGCTGCATG ARG149TRP CGCCACCAGCCCAGTGAGTAGGATCACCGCCCTGCCCAGG CGG to TGG CCTGGGCAGGGCGGTGATCCTACTCACTGGGCTGGTGGCGC 82 ATGCAGCACAGGATGGACC G GGCCTTGACCCCGAAGTCTCG CTCCCCCTCCTGCAGGCCCTGGCCCACTAGGGCCACCAC TCAAGGCC C GGTCCATC 83 GATGGACC G GGCCTTGA 84 Adenosine deaminase CTAGTGGGCCAGGGCCTGCAGGAGGGGGAGCGAGACTTCG 85 deficiency GGGTCAAGGCCCGGTCCATC C TGTGCTGCATGCGCCACCAG LEU152MET CCCAGTGAGTAGGATCACCGCCCTGCCCAGGGCCGCCCGT CTG to ATG ACGGGCGGCCCTGGGCAGGGCGGTGATCCTACTCACTGGG 86 CTGGTGGCGCATGCAGCACA G GATGGACCGGGCCTTGACCC CGAAGTCTCGCTCCCCCTCCTGCAGGCCCTGGCCCACTAG GGTCCATC C TGTGCTGC 87 GCAGCACA G GATGGACC 88 Adenosine deaminase GGCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCCC 89 deficiency GGTCCATCCTGTGCTGCATG C GCCACCAGCCCAGTGAGTAG ARG156CYS GATCACCGCCCTGCCCAGGGCCGCCCGTCTCACCCTGGCC CGC to TGC GGCCAGGGTGAGACGGGCGGCCCTGGGCAGGGCGGTGATC 90 CTACTCACTGGGCTGGTGGC G CATGCAGCACAGGATGGACC GGGCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCC GCTGCATG C GCCACCAG 91 CTGGTGGC G CATGCAGC 92 Adenosine deaminase GCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCCCG 93 deficiency GTCCATCCTGTGCTGCATGC G CCACCAGCCCAGTGAGTAGG ARG156HIS ATCACCGCCCTGCCCAGGGCCGCCCGTCTCACCCTGGCCC CGC to CAC GGGCCAGGGTGAGACGGGCGGCCCTGGGCAGGGCGGTGAT 94 CCTACTCACTGGGCTGGTGG C GCATGCAGCACAGGATGGAC CGGGCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGC CTGCATGC G CCACCAGC 95 GCTGGTGG C GCATGCAG 96 Adenosine deaminase CTGCCCACAGACTGGTCCCCCAAGGTGGTGGAGCTGTGTAA 97 deficiency GAAGTACCAGCAGCAGACC G TGGTAGCCATTGACCTGGCTG VAL177MET GAGATGAGACCATCCCAGGAAGCAGCCTCTTGCCTGGAC GTG to ATG GTCCAGGCAAGAGGCTGCTTCCTGGGATGGTCTCATCTCCAG 98 CCAGGTCAATGGCTACCA C GGTCTGCTGCTGGTACTTCTTAC ACAGCTCCACCACCTTGGGGGACCAGTCTGTGGGCAG AGCAGACC G TGGTAGCC 99 GGCTACCA C GGTCTGCT 100 Adenosine deaminase CAGACTGGTCCCCCAAGGTGGTGGAGCTGTGTAAGAAGTAC 101 deficiency CAGCAGCAGACCGTGGTAG C CATTGACCTGGCTGGAGATGA ALA179ASP GACCATCCCAGGAAGCAGCCTCTTGCCTGGACATGTCCA GCC to GAC TGGACATGTCCAGGCAAGAGGCTGCTTCCTGGGATGGTCTCA 102 TCTCCAGCCAGGTCAATG G CTACCACGGTCTGCTGCTGGTAC TTCTTACACAGCTCCACCACCTTGGGGGACCAGTCTG CGTGGTAG C CATTGACC 103 GGTCAATG G CTACCACG 104 Adenosine deaminase CCATTGACCTGGCTGGAGATGAGACCATCCCAGGAAGCAGC 105 deficiency CTCTTGCCTGGACATGTCC A GGCCTACCAGGTGGGTCCTGT GLN199PRO GAGAAGGAATGGAGAGGCTGGCCCTGGGTGAGCTTGTCT CAG to CCG AGACAAGCTCACCCAGGGCCAGCCTCTCCATTCCTTCTCACA 106 GGACCCACCTGGTAGGCC T GGACATGTCCAGGCAAGAGGCT GCTTCCTGGGATGGTCTCATCTCCAGCCAGGTCAATGG ACATGTCC A GGCCTACC 107 GGTAGGCC T GGACATGT 108 Adenosine deaminase GCTAGGGCACCCATGACCTGGCTCTCCCCCTTCCAGGAGGC 109 deficiency TGTGAAGAGCGGCATTCAC C GTACTGTCCACGCCGGGGAGG ARG211CYS TGGGCTCGGCCGAAGTAGTAAAAGAGGTGAGGGCCTGGG CGT to TGT CCCAGGCCCTCACCTCTTTTACTACTTCGGCCGAGCCCACCT 110 CCCCGGCGTGGACAGTAC G GTGAATGCCGCTCTTCACAGCC TCCTGGAAGGGGGAGAGCCAGGTCATGGGTGCCCTAGC GCATTCAC C GTACTGTC 111 GACAGTAC G GTGAATGC 112 Adenosine deaminase CTAGGGCACCCATGACCTGGCTCTCCCCCTTCCAGGAGGCT 113 deficiency GTGAAGAGCGGCATTCACC G TACTGTCCACGCCGGGGAGGT ARG211HIS GGGCTCGGCCGAAGTAGTAAAAGAGGTGAGGGCCTGGGC CGT to CAT GCCCAGGCCCTCACCTCTTTTACTACTTCGGCCGAGCCCACC 114 TCCCCGGCGTGGACAGTA C GGTGAATGCCGCTCTTCACAGC CTCCTGGAAGGGGGAGAGCCAGGTCATGGGTGCCCTAG CATTCACC G TACTGTGC 115 GGACAGTA C GGTGAATG 116 Adenosine deaminase ATGACCTGGCTCTCCCCCTTCCAGGAGGCTGTGAAGAGCGG 117 deficiency CATTCACCGTACTGTCCAC G CCGGGGAGGTGGGCTCGGCCG ALA215THR AAGTAGTAAAAGAGGTGAGGGCCTGGGCTGGCCATGGGG GCC to ACC CCCCATGGCCAGCGCAGGCCCTCACCTCTTTTACTACTTCGG 118 CCGAGCCCACCTCCCCGG C GTGGACAGTACGGTGAATGCCG CTCTTCACAGCCTCCTGGAAGGGGGAGAGCCAGGTCAT CTGTCCAC G CCGGGGAG 119 CTCCCCGG C GTGGACAG 120 Adenosine deaminase ACCTGGCTCTCCCCCTTCCAGGAGGCTGTGAAGAGCGGCAT 121 deficiency TCACCGTACTGTCCACGCC G GGGAGGTGGGCTCGGCCGAAG GLY216ARG TAGTAAAAGAGGTGAGGGCCTGGGCTGGCCATGGGGTCC GGG to AGG GGACCCCATGGCCAGCCCAGGCCCTCACCTCTTTTACTACTT 122 CGGCCGAGCCCACCTCCC C GGCGTGGACAGTACGGTGAATG CCGCTCTTCACAGCCTCCTGGAAGGGGGAGAGCCAGGT TCCACGCC G GGGAGGTG 123 CACCTCCC C GGCGTGGA 124 Adenosine deaminase TGGCTCTCCCCCTTCCAGGAGGCTGTGAAGAGCGGCATTCA 125 deficiency CCGTACTGTCCACGCCGGG G AGGTGGGCTCGGCCGAAGTAG GLU217LYS TAAAAGAGGTGAGGGCCTGGGCTGGCCATGGGGTCCCTC GAG to AAG GAGGGACCCCATGGCCAGCCCAGGCCCTCACCTCTTTTACTA 126 CTTCGGCCGAGCCCACCT C CCCGGCGTGGACAGTACGGTGA ATGCCGCTCTTCACAGCCTCCTGGAAGGGGGAGAGCCA ACGCCGGG G AGGTGGGC 127 GCCCACCT C CCCGGCGT 128 Adenosine deaminase CTGCCTCCTCCCATACTTGGCTCTATTCTGCTTCTCTACAGGC 129 deficiency TGTGGACATACTCAAGA C AGAGCGGCTGGGACACGGCTACC THR233ILE ACACCCTGGAAGACCAGGCCCTTTATAACAGGCTGCG ACA to ATA CGCAGCCTGTTATAAAGGGCCTGGTCTTCCAGGGTGTGGTAG 130 CCGTGTCCCAGCCGCTCT G TCTTGAGTATGTCCACAGCCTGT AGAGAAGCAGAATAGAGCCAAGTATGGGAGGAGGCAG ACTCAAGA C AGAGCGGC 131 GCCGCTCT G TCTTGAGT 132 Adenosine deaminase CAGAGCGGCTGGGACACGGCTACCACACCCTGGAAGACCAG 133 deficiency GCCCTTTATAACAGGCTGC G GCAGGAAAACATGCACTTCGAG ARG253PRO GTAAGCGGGCCAGGGAGTGGGGAGGAACCATCCCCGGC CGG to CCG GCCGGGGATGGTTCCTCCCCACTCCCTGGCCCGCTTACCTC 134 GAAGTGCATGTTTTCCTGC C GCAGCCTGTTATAAAGGGCCTG GTCTTCCAGGGTGTGGTAGCCGTGTCCCAGCCGCTCTG CAGGCTGC G GCAGGAAA 135 TTTCCTGC C GCAGCCTG 136 Adenosine deaminase GAGCGGCTGGGACACGGCTACCACACCCTGGAAGACCAGGC 137 deficiency CCTTTATAACAGGCTGCGG C AGGAAAACATGCACTTCGAGGT GLN254TERM AAGCGGGCCAGGGAGTGGGGAGGAACCATCCCCGGCTG CAG to TAG CAGCCGGGGATGGTTCCTCCCCACTCCCTGGCCCGCTTACC 138 TCGAAGTGCATGTTTTCCT G CCGCAGCCTGTTATAAAGGGCC TGGTCTTCCAGGGTGTGGTAGCCGTGTCCCAGCCGCTC GGCTGCGG C AGGAAAAC 139 GTTTTCCT G CCGCAGCC 140 Adenosine deaminase CCACACACCTGCTCTTCCAGATCTGCCCCTGGTCCAGCTACC 141 deficiency TCACTGGTGCCTGGAAGC C GGACACGGAGCATGCAGTCATT PRO274LEU CGGTGAGCTCTGTTCCCCTGGGCCTGTTCAATTTTGTT CCG to CTG AACAAAATTGAACAGGCCCAGGGGAACAGAGCTCACCGAATG 142 ACTGCATGCTCCGTGTCC G GCTTCCAGGCACCAGTGAGGTA GCTGGACCAGGGGCAGATCTGGAAGAGCAGGTGTGTGG CTGGAAGC C GGACACGG 143 CCGTGTCC G GCTTCCAG 144 Adenosine deaminase GGAGGCTGATTCTCTCCTCCTCCCTCTTCTGCAGGCTCAAAA 145 deficiency ATGACCAGGCTAACTACT C GCTCAACACAGATGACCCGCTCA SER291LEU TCTTCAAGTCCACCCTGGACACTGATTACCAGATGAC TCG to TTG GTCATCTGGTAATCAGTGTCCAGGGTGGACTTGAAGATGAGC 146 GGGTCATCTGTGTTGAGC G AGTAGTTAGCCTGGTCATTTTTGA GCCTGCAGAAGAGGGAGGAGGAGAGAATCAGCCTCC TAACTACT C GCTCAACA 147 TGTTGAGC G AGTAGTTA 148 Adenosine deaminase CCTCCCTCTTCTGCAGGCTCAAAAATGACCAGGCTAACTACT 149 deficiency CGCTCAACACAGATGACC C GCTCATCTTCAAGTCCACCCTGG PRO297GLN ACACTGATTACCAGATGACCAAACGGGACATGGGCTT CCG to CAG AAGCCCATGTCCCGTTTGGTCATCTGGTAATCAGTGTCCAGG 150 GTGGACTTGAAGATGAGC G GGTCATCTGTGTTGAGCGAGTAG TTAGCCTGGTCATTTTTGAGCCTGCAGAAGAGGGAGG AGATGACC C GCTCATCT 151 AGATGAGC G GGTCATCT 152 Adenosine deaminase AAAATGACCAGGCTAACTACTCGCTCAACACAGATGACCCGC 153 deficiency TCATCTTCAAGTCCACCC T GGACACTGATTACCAGATGACCAA LEU304ARG ACGGGACATGGGCTTTACTGAAGAGGAGTTTAAAAG CTG to CGG CTTTTAAACTCCTCTTCAGTAAAGCCCATGTCCCGTTTGGTCA 154 TCTGGTAATCAGTGTCC A GGGTGGACTTGAAGATGAGCGGGT CATCTGTGTTGAGCGAGTAGTTAGCCTGGTCATTTT GTCCACCC T GGACACTG 155 CAGTGTCC A GGGTGGAC 156 Adenosine deaminase GCCTTCTTTGTTCTCTGGTTCCATGTTGTCTGCCATTCTGGCC 157 deficiency TTTCCAGAACATCAATG C GGCCAAATCTAGTTTCCTCCCAGAA ALA329TAL GATGAAAAGAGGGAGCTTCTCGACCTGCTCTATAA C-to-T at base 1081 TTATAGAGCAGGTCGAGAAGCTCCCTCTTTTCATCTTCTGGGA 158 GGAAACTAGATTTGGCC G CATTGATGTTCTGGAAAGGCCAGA ATGGCAGACAACATGGAACCAGAGAACAAAGAAGGC CATCAATG C GGCCAAAT 159 ATTTGGCC G CATTGATG 160

EXAMPLE 5 P53 Mutations

The p53 gene codes for a protein that acts as a transcription factor and serves as a key regulator of the cell cycle. Mutation in this gene is probably the most significant genetic change characterizing the transformation of cells from normalcy to malignancy.

Inactivation of p53 by mutation disrupts the cell cycle which, in turn, sets the stage for tumor formation. Mutations in the p53 gene are among the most commonly diagnosed genetic disorders, occuring in as many as 50% of cancer patients. For some types of cancer, most notably of the breast, lung and colon, p53 mutations are the predominant genetic alternations found thus far. These mutations are associated with genomic instability and thus an increased susceptibility to cancer. Some p53 lesions result in malignancies that are resistant to the most widely used therapeutic regimens and therefore demand more aggressive treatment.

That p53 is associated with different malignant tumors is illustrated in the Li-Fraumeni autosomal dominant hereditary disorder characterized by familial multiple tumors due to mutation in the p53 gene. Affected individuals can develop one or more tumors, including: brain (12%); soft-tissue sarcoma (12%); breast cancer (25%); adrenal tumors (1%); bone cancer (osteosarcoma) (6%); cancer of the lung, prostate, pancreas, and colon as well as lymphoma and melanoma can also occur.

Certain of the most frequently mutated codons are codons 175, 248 and 273, however a variety of oligonucleotides are described below in the atttached table.

TABLE 11 p53 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: In 2 families with GACTGTACCACCATCCACTACAACTACATGTGTAACAGTTCCT 161 Li-Fraumeni GCATGGGCGGCATGAAC C GGAGGCCCATCCTCACCATCATC syndrome, there was a ACACTGGAAGACTCCAGGTCAGGAGCCACTTGCCACC C-to-T mutation at the first nucleotide of GGTGGCAAGTGGCTCCTGACCTGGAGTCTTCCAGTGTGATGA 162 codon 248 which TGGTGAGGATGGGCCTCC G GTTCATGCCGCCCATGCAGGAA changed arginine to CTGTTACACATGTAGTTGTAGTGGATGGTGGTACAGTC tryptophan. GCATGAACCGGAGGCCC 163 GGGCCTCC G GTTCATGC 164 In a family with the TGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGGCCCAT 165 Li-Fraumeni CCTCACCATCATCACACTG G AAGACTCCAGGTCAGGAGCCAC syndrome, a G-to-A TTGCCACCCTGCACACTGGCCTGCTGTGCCCCAGCCTC mutation at the first nucleotide of codon GAGGCTGGGGCACAGCAGGCCAGTGTGCAGGGTGGCAAGT 166 258 resulting in the GGCTCCTGACCTGGAGTCTT C CAGTGTGATGATGGTGAGGAT substitution of lysine GGGCCTCCGGTTCATGCCGCCCATGCAGGAACTGTTACA for glutamic acid. TCACACTG G AAGACTCC 167 GGAGTCTT C CAGTGTGA 168 In a family with the GTTGGCTCTGACTGTACCACCATCCACTACAACTACATGTGTA 169 Li-Fraumeni ACAGTTCCTGCATGGGC G GCATGAACCGGAGGCCCATCCTC syndrome, a G-to-T ACCATCATCACACTGGAAGACTCCAGGTCAGGAGCCA mutation at the first nucleotide of codon 245 resulting in the substitution of cysteine for glycine. A gly245-to-ser, TGGCTCCTGACCTGGAGTCTTCCAGTGTGATGATGGTGAGGA 170 GGC-to-AGC, TGGGCCTCCGGTTCATGC C GCCCATGCAGGAACTGTTACACA mutation was found in TGTAGTTGTAGTGGATGGTGGTACAGTCAGAGCCAAC a patient in whom osteosarcoma was GCATGGGC G GCATGAAC 171 diagnosed at the age of 18 years. GTTCATGC C GCCCATGC 172 In a family with the TCCACTACAACTACATGTGTAACAGTTCCTGCATGGGCGGCA 173 Li-Fraumeni TGAACCGGAGGCCCATCC T CACCATCATCACACTGGAAGACT syndrome, a germline CCAGGTCAGGAGCCACTTGCCACCCTGCACACTGGCC mutation at codon 252: a T-to-C change at the GGCCAGTGTGCAGGGTGGCAAGTGGCTCCTGACCTGGAGTC 174 second position TTCCAGTGTGATGATGGTG A GGATGGGCCTCCGGTTCATGCC resulted in substitution GCCCATGCAGGAACTGTTACACATGTAGTTGTAGTGGA of proline for leucine. GCCCATCC T CACCATCA 175 TGATGGTG A GGATGGGC 176 Researchers analyzed TACCACCATCCACTACAACTACATGTGTAACAGTTCCTGCATG 177 for mutations in p53 GGCGGCATGAACCGGAG G CCCATCCTCACCATCATCACACT hepatocellular GGAAGACTCCAGGTCAGGAGCCACTTGCCACCCTGCA carcinomas from patents in Qidong, an TGCAGGGTGGCAAGTGGCTCCTGACCTGGAGTCTTCCAGTG 178 area of high incidence TGATGATGGTGAGGATGGG C CTCCGGTTCATGCCGCCCATG in China, in which both CAGGAACTGTTACACATGTAGTTGTAGTGGATGGTGGTA hepatitis B virus and aflatoxin B1 are risk AACCGGAG G CCCATCCT 179 factors. Eight of 16 tumors had a point AGGATGGG C CTCCGGTT 180 mutation at the third base position of codon 249. The G-to-T mutation at codon 249 led to a change from arginine to serine (AGG to AGT). In cases of CTGGCCAAGACCTGCCCTGTGCAGCTGTGGGTTGATTCCACA 181 hepatocellular CCCCCGCCCGGCACCCGC G TCCGCGCCATGGCCATCTACAA carcinoma in southern GCAGTCACAGCACATGACGGAGGTTGTGAGGCGCTGCC Africa, a G-to-T substitution in codon GGCAGCGCCTCACAACCTCCGTCATGTGCTGTGACTGCTTGT 182 157 resulting in a AGATGGCCATGGCGCGGA C GCGGGTGCCGGGCGGGGGTGT change from valine to GGAATCAACCCACAGCTGCACAGGGCAGGTCTTGGCCAG phenylahanine. GCACCCGC G TCCGCGCC 183 GGCGCGGA C GCGGGTGC 184 In a family with TTGGCTCTGACTGTACCACCATCCACTACAACTACATGTGTAA 185 Li-Fraumeni in which CAGTTCCTGCATGGGCG G CATGAACCGGAGGCCCATCCTCA noncancerous skin CCATCATCACACTGGAAGACTCCAGGTCAGGAGCCAC fibroblasts from affected individuals GTGGCTCCTGACCTGGAGTCTTCCAGTGTGATGATGGTGAGG 186 showed an unusual ATGGGCCTCCGGTTCATG C CGCCCATGCAGGAACTGTTACAC radiation-resistant ATGTAGTTGTAGTGGATGGTGGTACAGTCAGAGCCAA phenotype, a point mutation in codon 245 CATGGGCG G CATGAACC 187 of the P53 gene. A change from GGC to GGTTCATG C CGCCCATG 188 GAC predicted substitution of aspartic acid for glycine. In 2 of 8 families with ACTGTACCACCATCCACTACAACTACATGTGTAACAGTTCCTG 189 Li-Fraumeni CATGGGCGGCATGAACC G GAGGCCCATCCTCACCATCATCA syndrome, a mutation CACTGGAAGACTCCAGGTCAGGAGCCACTTGCCACCC in codon 248: a GGGTGGCAAGTGGCTCCTGACCTGGAGTCTTCCAGTGTGAT 190 CGG-to-CAG change GATGGTGAGGATGGGCCTC C GGTTCATGCCGCCCATGCAGG resulting in substitution AACTGTTACACATGTAGTTGTAGTGGATGGTGGTACAGT of glutamine for arginine. CATGAACC G GAGGCCCA 191 TGGGCCTC C GGTTCATG 192 In 9 members of an CCCTGACTTTCAACTCTGTCTCCTTCCTCTTCCTACAGTACTC 193 extended family with CCCTGCCCTCAACAAGA T GTTTTGCCAACTGGCCAAGACCTG Li-Fraumeni CCCTGTGCAGCTGTGGGTTGATTCCACACCCCCGCC syndrome, a germline mutation at codon 133 GGCGGGGGTGTGGAATCAACCCACAGCTGCACAGGGCAGGT 194 (ATG-to-ACG), CTTGGCCAGTTGGCAAAAC A TCTTGTTGAGGGCAGGGGAGTA resulted in the CTGTAGGAAGAGGAAGGAGACAGAGTTGAAAGTCAGGG substitution of threonine for CAACAAGA T GTTTTGCC 195 methionine (M133T), and completely GGCAAAAC A TCTTGTTG 196 cosegregated with the cancer syndrome. In 1 pedigree TCTTGCTTCTCTTTTCCTATCCTGAGTAGTGGTAATCTACTGG 197 consistent with the GACGGAACAGCTTTGAG G TGCGTGTTTGTGCCTGTCCTGGGA Li-Fraumeni GAGACCGGCGCACAGAGGAAGAGAATCTCCGCAAGA syndrome, a germline G-to-T transversion at TCTTGCGGAGATTCTCTTCCTCTGTGCGCCGGTCTCTCCCAG 198 codon 272 (valine to GACAGGCACAAACACGCA C CTCAAAGCTGTTCCGTCCCAGTA leucine) was found. GATTACCACTACTCAGGATAGGAAAAGAGAAGCAAGA GCTTTGAG G TGCGTGTT 199 AACACGCA C CTCAAAGC 200 A ser241-to-phe TTATCTCCTAGGTTGGCTCTGACTGTACCACCATCCACTACAA 201 mutation due to a CTACATGTGTAACAGTT C CTGCATGGGCGGCATGAACCGGAG TCC-to-TTC change GCCCATCCTCACCATCATCACACTGGAAGACTCCAG was found in a patient with hepatoblastoma CTGGAGTCTTCCAGTGTGATGATGGTGAGGATGGGCCTCCG 202 and multiple foci of GTTCATGCCGCCCATGCAG G AACTGTTACACATGTAGTTGTA osteosarcoma. GTGGATGGTGGTACAGTCAGAGCCAACCTAGGAGATAA TAACAGTT C CTGCATGG 203 CCATGCAG G AACTGTTA 204 An AAG-to-TAG CAGAAAACCTACCAGGGCAGCTACGGTTTCCGTCTGGGCTTC 205 change of codon 120, TTGCATTCTGGGACAGCC A AGTCTGTGACTTGCACGGTCAGT resulting in conversion TGCCCTGAGGGGCTGGCTTCCATGAGACTTCAATGCC from lysine to a stop codon, was found in a GGCATTGAAGTCTCATGGAAGCCAGCCCCTCAGGGCAACTG 206 patient with ACCGTGCAAGTCACAGACT T GGCTGTCCCAGAATGCAAGAAG osteosarcoma and CCCAGACGGAAACCGTAGCTGCCCTGGTAGGTTTTCTG adenocarcinoma of the lung at age 18 and GGACAGCC A AGTCTGTG 207 brain tumor (glioma) at the age of 27. CACAGACT T GGCTGTCC 208 A CGG-to-TGG GGTAATCTACTGGGACGGAACAGCTTTGAGGTGCGTGTTTGT 209 change at codon 282, GCCTGTCCTGGGAGAGAC C GGCGCACAGAGGAAGAGAATCT resulting in the CCGCAAGAAAGGGGAGCCTCACCACGAGCTGCCCCCAG substitution of tryptophan for arginine, CTGGGGGCAGCTCGTGGTGAGGCTCCCCTTTCTTGCGGAGA 210 was found in a TTCTCTTCCTCTGTGCGCC G GTCTCTCCCAGGACAGGCACAA patient who developed ACACGCACCTCAAAGCTGTTCCGTCCCAGTAGATTACC osteosarcoma at the age of 10 years. GGAGAGAC C GGCGCACA 211 TGTGCGCC G GTCTCTCC 212 In 5 of 6 anaplastic GCTTCTCTTTTCCTATCCTGAGTAGTGGTAATCTACTGGGACG 213 carcinomas of the GAACAGCTTTGAGGTGC G TGTTTGTGCCTGTCCTGGGAGAGA thyroid and in an CCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAGG anaplastic carcinoma thyroid cell line ARO, a CCTTTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGGTCTCTC 214 CGT-to-CAT mutation CCAGGACAGGCACAAACA C GCACCTCAAAGCTGTTCCGTCCC converted AGTAGATTACCACTACTCAGGATAGGAAAAGAGAAGC arginine-273 to histidine. TGAGGTGC G TGTTTGTG 215 CACAAACA C GCACCTCA 216 A germline TCCTAGCACTGCCCAACAACACCAGCTCCTCTCCCCAGCCAA 217 GGA-to-GTA mutation AGAAGAAACCACTGGATG G AGAATATTTCACCCTTCAGGTACT resulting in a change AAGTCTTGGGACCTCTTATCAAGTGGAAAGTTTCCA of glycine-325 to valine TGGAAACTTTCCACTTGATAAGAGGTCCCAAGACTTAGTACCT 218 was found in a patient GAAGGGTGAAATATTCT C CATCCAGTGGTTTCTTCTTTGGCTG who had non-Hodgkin GGGAGAGGAGCTGGTGTTGTTGGGCAGTGCTAGGAA lymphoma diagnosed at age 17 and colon ACTGGATG G AGAATATT 219 carcinoma at age 26. AATATTCT C CATCCAGT 220 CGC-CCC AATGGTTCACTGAAGACCCAGGTCCAGATGAAGCTCCCAGAA 221 Arg-72 to Pro TGCCAGAGGCTGCTCCCC G CGTGGCCCCTGCACCAGCAGCT association with Lung CCTACACCGGCGGCCCCTGCACCAGCCCCCTCCTGGCC cancer GGCCAGGAGGGGGCTGGTGCAGGGGCCGCCGGTGTAGGAG 222 CTGCTGGTGCAGGGGCCACG C GGGGAGCAGCCTCTGGCATT CTGGGAGCTTCATCTGGACCTGGGTCTTCAGTGAACCATT TGCTCCCC G CGTGGCCC 223 GGGCCACG C GGGGAGCA 224 CCG-CTG AAGCTCCCAGAATGCCAGAGGCTGCTCCCCGCGTGGCCCCT 225 Pro-82 to Leu GCACCAGCAGCTCCTACAC C GGCGGCCCCTGCACCAGCCCC Breast cancer CTCCTGGCCCCTGTCATCTTCTGTCCCTTCCCAGAAAAC GTTTTCTGGGAAGGGACAGAAGATGACAGGGGCCAGGAGGG 226 GGCTGGTGCAGGGGCCGCC G GTGTAGGAGCTGCTGGTGCA GGGGCCACGCGGGGAGCAGCCTCTGGCATTCTGGGAGCTT TCCTACAC C GGCGGCCC 227 GGGCCGCC G GTGTAGGA 228 cCAA-TAA TTCAACTCTGTCTCCTTCCTCTTCCTACAGTACTCCCCTGCCC 229 Gln-136 to Term TCAACAAGATGTTTTGC C AACTGGCCAAGACCTGCCCTGTGC Li-Fraumeni syndrome AGCTGTGGGTTGATTCCACACCCCCGCCCGGCACCC GGGTGCCGGGCGGGGGTGTGGAATCAACCCACAGCTGCACA 230 GGGCAGGTCTTGGCCAGTT G GCAAAACATCTTGTTGAGGGCA GGGGAGTACTGTAGGAAGAGGAAGGAGACAGAGTTGAA TGTTTTGC C AACTGGCC 231 GGCCAGTT G GCAAAACA 232 TGC-TAC TCCTCTTCCTACAGTACTCCCCTGCCCTCAACAAGATGTTTTG 233 Cys-141 to Tyr CCAACTGGCCAAGACCT G CCCTGTGCAGCTGTGGGTTGATTC Li-Fraumeni syndrome CACACCCCCGCCCGGCACCCGCGTCCGCGCCATGGC GCCATGGCGCGGACGCGGGTGCCGGGCGGGGGTGTGGAAT 234 CAACCCACAGCTGCACAGGG C AGGTCTTGGCCAGTTGGCAA AACATCTTGTTGAGGGCAGGGGAGTACTGTAGGAAGAGGA CAAGACCT G CCCTGTGC 235 GCACAGGG C AGGTCTTG 236 aCCC-TCC AACAAGATGTTTTGCCAACTGGCCAAGACCTGCCCTGTGCAG 237 Pro-151 to Ser CTGTGGGTTGATTCCACA C CCCCGCCCGGCACCCGCGTCCG Li-Fraumeni syndrome CGCCATGGCCATCTACAAGCAGTCACAGCACATGACGG CCGTCATGTGCTGTGACTGCTTGTAGATGGCCATGGCGCGG 238 ACGCGGGTGCCGGGCGGGG G TGTGGAATCAACCCACAGCT GCACAGGGCAGGTCTTGGCCAGTTGGCAAAACATCTTGTT ATTCCACA C CCCCGCCC 239 GGGCGGGG G TGTGGAAT 240 CCG-CTG AGATGTTTTGCCAACTGGCCAAGACCTGCCCTGTGCAGCTGT 241 Pro-152 to Leu GGGTTGATTCCACACCCC C GCCCGGCACCCGCGTCCGCGCC Adrenocortical ATGGCCATCTACAAGCAGTCACAGCACATGACGGAGGT carcinoma ACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGCCATGGCG 242 CGGACGCGGGTGCCGGGC G GGGGTGTGGAATCAACCCACA GCTGCACAGGGCAGGTCTTGGCCAGTTGGCAAAACATCT CACACCCC C GCCCGGCA 243 TGCCGGGC G GGGGTGTG 244 GGC-GTC TTTGCCAACTGGCCAAGACCTGCCCTGTGCAGCTGTGGGTTG 245 Gly-154 to Val ATTCCACACCCCCGCCCG G CACCCGCGTCCGCGCCATGGCC Glioblastoma ATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAG CTCACAACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGCC 246 ATGGCGCGGACGCGGGTG C CGGGCGGGGGTGTGGAATCAA CCCACAGCTGCACAGGGCAGGTCTTGGCCAGTTGGCAAA CCCGCCCG G CACCCGCG 247 CGCGGGTG C CGGGCGGG 248 CGC-CAC CCCGCGTCCGCGCCATGGCCATCTACAAGCAGTCACAGCAC 249 Arg-175 to His ATGACGGAGGTTGTGAGGC G CTGCCCCCACCATGAGCGCTG Li-Fraumeni syndrome CTCAGATAGCGATGGTGAGCAGCTGGGGCTGGAGAGACG CGTCTCTCCAGCCCCAGCTGCTCACCATCGCTATCTGAGCAG 250 CGCTCATGGTGGGGGCAG C GCCTCACAACCTCCGTCATGTG CTGTGACTGCTTGTAGATGGCCATGGCGCGGACGCGGG TGTGAGGC G CTGCCCCC 251 GGGGGCAG C GCCTCACA 252 tGAG-AAG ATGGCCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTG 253 GTu-180 to Lys AGGCGCTGCCCCCACCAT G AGCGCTGCTCAGATAGCGATGG Li-Fraumeni syndrome TGAGCAGCTGGGGCTGGAGAGACGACAGGGCTGGTTGC GCAACCAGCCCTGTCGTCTCTCCAGCCCCAGCTGCTCACCAT 254 CGCTATCTGAGCAGCGCT C ATGGTGGGGGCAGCGCCTCACA ACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGCCAT CCCACCAT G AGCGCTGC 255 GCAGCGCT C ATGGTGGG 256 gCGC-TGC GCCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAGG 257 Arg-181 to Cys CGCTGCCCCCACCATGAG C GCTGCTCAGATAGCGATGGTGA Breast cancer GCAGCTGGGGCTGGAGAGACGACAGGGCTGGTTGCCCA TGGGCAACCAGCCCTGTCGTCTCTCCAGCCCCAGCTGCTCA 258 CCATCGCTATCTGAGCAGC G CTCATGGTGGGGGCAGCGCCT CACAACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGC ACCATGAG C GCTGCTCA 259 TGAGCAGC G CTCATGGT 260 CGC-CAC CCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAGGC 261 Arg-81 to His GCTGCCCCCACCATGAGC G CTGCTCAGATAGCGATGGTGAG Breast cancer CAGCTGGGGCTGGAGAGACGACAGGGCTGGTTGCCCAG CTGGGCAACCAGCCCTGTCGTCTCTCCAGCCCCAGCTGCTC 262 ACCATCGCTATCTGAGCAG C GCTCATGGTGGGGGCAGCGCC TCACAACCTCCGTCATGTGCTGTGACTGCTTGTAGATGG CCATGAGC G CTGCTCAG 263 CTGAGCAG C GCTCATGG 264 CAT-CGT CCAGGGTCCCCAGGCCTCTGATTCCTCACTGATTGCTCTTAG 265 His-193 to Arg GTCTGGCCCCTCCTCAGC A TCTTATCCGAGTGGAAGGAAATT Li-Fraumeni syndrome TGCGTGTGGAGTATTTGGATGACAGAAACACTTTTCG CGAAAAGTGTTTCTGTCATCCAAATACTCCACACGCAAATTTC 266 CTTCCACTCGGATAAGA T GCTGAGGAGGGGCCAGACCTAAGA GCAATCAGTGAGGAATCAGAGGCCTGGGGACCCTGG TCCTCAGC A TCTTATCC 267 GGATAAGA T GCTGAGGA 268 cCGA-TGA CCCAGGCCTCTGATTCCTCACTGATTGCTCTTAGGTCTGGCC 269 Arg-196 to Term CCTCCTCAGCATCTTATC C GAGTGGAAGGAAATTTGCGTGTG Adrenocortical GAGTATTTGGATGACAGAAACACTTTTCGACATAGTG carcinoma CACTATGTCGAAAAGTGTTTCTGTCATCCAAATACTCCACACG 270 CAAATTTCCTTCCACT C GGATAAGATGCTGAGGAGGGGCCAG ACCTAAGAGCAATCAGTGAGGAATCAGAGGCCTGGG ATCTTATC C GAGTGGAA 271 TTCCACTC G GATAAGAT 272 cAGA-TGA GCCCCTCCTCAGCATCTTATCCGAGTGGAAGGAAATTTGCGT 273 Arg-209 to Term GTGGAGTATTTGGATGAC A GAAACACTTTTCGACATAGTGTG Li-Fraumeni syndrome GTGGTGCCCTATGAGCCGCCTGAGGTCTGGTTTGCAA TTGCAAACCAGACCTCAGGCGGCTCATAGGGCACCACCACA 274 CTATGTCGAAAAGTGTTTC T GTCATCCAAATACTCCACACGCA AATTTCCTTCCACTCGGATAAGATGCTGAGGAGGGGC TGGATGAC A GAAACACT 275 AGTGTTTC T GTCATCCA 276 tCGA-TGA CATCTTATCCGAGTGGAAGGAAATTTGCGTGTGGAGTATTTG 277 Arg-213 to Term GATGACAGAAACACTTTT C GACATAGTGTGGTGGTGCCCTAT Li-Fraumeni syndrome GAGCCGCCTGAGGTCTGGTTTGCAACTGGGGTCTCTG CAGAGACCCCAGTTGCAAACCAGACCTCAGGCGGCTCATAG 278 GGCACCACCACACTATGTC G AAAAGTGTTTCTGTCATCCAAAT ACTCCACACGCAAATTTCCTTCCACTCGGATAAGATG ACACTTTT C GACATAGT 279 ACTATGTC G AAAAGTGT 280 gCCC-TCC GGAAATTTGCGTGTGGAGTATTTGGATGACAGAAACACTTTTC 281 Pro-219 to Ser GACATAGTGTGGTGGTG C CCTATGAGCCGCCTGAGGTCTGG Adrenocortical TTTGCAACTGGGGTCTCTGGGAGGAGGGGTTAAGGGT carcinoma ACCCTTAACCCCTCCTCCCAGAGACCCCAGTTGCAAACCAGA 282 CCTCAGGCGGCTCATAGG G CACCACCACACTATGTCGAAAAG TGTTTCTGTCATCCAAATACTCCACACGCAAATTTCC TGGTGGTG C CCTATGAG 283 CTCATAGG G CACCACCA 284 TAT-TGT ATTTGCGTGTGGAGTATTTGGATGACAGAAACACTTTTCGACA 285 Tyr-220 to Cys TAGTGTGGTGGTGCCCT A TGAGCCGCCTGAGGTCTGGTTTG Li-Fraumeni syndrome CAACTGGGGTCTCTGGGAGGAGGGGTTAAGGGTGGTT AACCACCCTTAACCCCTCCTCCCAGAGACCCCAGTTGCAAAC 286 CAGACCTCAGGCGGCTCA T AGGGCACCACCACACTATGTCG AAAAGTGTTTCTGTCATCCAAATACTCCACACGCAAAT GGTGCCCT A TGAGCCGC 287 GCGGCTCA T AGGGCACC 288 cTCT-ACT CACAGGTCTCCCCAAGGCGCACTGGCCTCATCTTTGGGCCTG 289 Ser-227 to Thr TGTTATCTCCTAGGTTGGC T CTGACTGTACCACCATCCACTAC Rhabdomyosarcoma AACTACATGTGTAACAGTTCCTGCATGGGCGGCATGA TCATGCCGCCCATGCAGGAACTGTTACACATGTAGTTGTAGT 290 GGATGGTGGTACAGTCAG A GCCAACCTAGGAGATAACACAG GCCCAAGATGAGGCCAGTGCGCCTTGGGGAGACCTGTG AGGTTGGC T CTGACTGT 291 ACAGTCAG A GCCAACCT 292 cCAC-AAC GCACTGGCCTCATCTTGGGCCTGTGTTATCTCCTAGGTTGGC 293 His-233 to Asn TCTGACTGTACCACCATC C ACTACAACTACATGTGTAACAGTT Glioma CCTGCATGGGCGGCATGAACCGGAGGCCCATCCTCA TGAGGATGGGCCTCCGGTTCATGCCGCCCATGCAGGAACTG 294 TTACACATGTAGTTGTAGT G GATGGTGGTACAGTCAGAGCCA ACCTAGGAGATAACACAGGCCCAAGATGAGGCCAGTGC CCACCATC C ACTACAAC 295 GTTGTAGT G GATGGTGG 296 cAAC-GAC GCCTCATCTTGGGCCTGTGTTATCTCCTAGGTTGGCTCTGAC 297 Asn-235 to Asp TGTACCACCATCCACTAC A ACTACATGTGTAACAGTTCCTGCA Adrenocortical TGGGCGGCATGAACCGGAGGCCCATCCTCACCATCA carcinoma TGATGGTGAGGATGGGCCTCCGGTTCATGCCGCCCATGCAG 298 GAACTGTTACACATGTAGT T GTAGTGGATGGTGGTACAGTCA GAGCCAACCTAGGAGATAACACAGGCCCAAGATGAGGC TCCACTAC A ACTACATG 299 CATGTAGT T GTAGTGGA 300 AAC-AGC CCTCATCTTGGGCCTGTGTTATCTCCTAGGTTGGCTCTGACT 301 Asn-235 to Ser GTACCACCATCCACTAC A ACTACATGTGTAACAGTTCCTGCAT Rhabdomyosarcoma GGGCGGCATGAACCGGAGGCCCATCCTCACCATCAT ATGATGGTGAGGATGGGCCTCCGGTTTCATGCCGCCCATGCA 302 GGAACTGTTACACATGTAG T TGTAGTGGATGGTGGTACAGTC AGAGCCAACCTAGGAGATAACACAGGCCCAAGATGAGG CCACTACA A CTACATGT 303 ACATGTAG T TGTAGTGG 304 ATCc-ATG CATCCACTACAACTACATGTGTAACAGTTCCTGCATGGGCGG 305 Ile-251 to Met CATGAACCGGAGGCCCAT C CTCACCATCATCACACTGGAAGA Glioma CTCCAGGTCAGGAGCCACTTGCCACCCTGCACACTGG CCAGTGTGCAGGGTGGCAAGTGGCTCCTGACGTGGAGTCTT 306 CCAGTGTGATGATGGTGAG G ATGGGCCTCCGGTTCATGCCG CCCATGCAGGAACTGTTACACATGTAGTTGTAGTGGATG AGGCCCAT C CTCACCAT 307 ATGGTGAG G ATGGGCCT 308 ACA-ATA ACATGTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGG 309 Thr-256 to Ile CCCATCCTCACCATCATCA C ACTGGAAGACTCCAGGTCAGGA Glioblastoma GCCACTTGCCACCCTGCACACTGGCCTGCTGTGCCCCA TGGGGCACAGCAGGCCAGTGTGCAGGGTGGCAAGTGGCTCC 310 TGACCTGGAGTCTTCCAGT G TGATGATGGTGAGGATGGGCCT CCGGTTCATGCCGCCCATGCAGGAACTGTTACACATGT CATCATCA C ACTGGAAG 311 CTTCCAGT G TGATGATG 312 CTG-CAG TGTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGGCCC 313 Leu-257 to Gln ATCCTCACCATCATCACAC T GGAAGACTCCAGGTCAGGAGCC Li-Fraumeni syndrome ACTTGCCACCCTGCACACTGGCCTGCTGTGCCCCAGCC GGCTGGGGCACAGCAGGCCAGTGTGCAGGGTGGCAAGTGG 314 CTCCTGACCTGGAGTCTTCC A GTGTGATGATGGTGAGGATGG GCCTCCGGTTCATGCCGCCCATGCAGGAACTGTTACACA CATCACAC T GGAAGACT 315 AGTCTTCC A GTGTGATG 316 CTG-CCG GACCTGATTTCCTTACTGCCTCTTGCTTCTCTTTTCCTATCCT 317 Leu-265 to Pro GAGTAGTGGTAATCTAC T GGGACGGAACAGCTTTGAGGTGCG Li-Fraumeni syndrome TGTTTGTGCCTGTCCTGGGAGAGACCGGCGCACAGA TCTGTGCGCCGGTCTCTCCCAGGACAGGCACAAACACGCAC 318 CTCAAAGCTGTTCCGTCCC A GTAGATTACCACTACTCAGGAT AGGAAAAGAGAAGCAAGAGGCAGTAAGGAAATCAGGTC TAATCTAC T GGGACGGA 319 TCCGTCCC A GTAGATTA 320 gCGT-TGT TGCTTCTCTTTTCCTATCCTGAGTAGTGGTAATCTACTGGGAC 321 Arg-273 to Cys GGAACAGCTTTGAGGTG C GTGTTTGTGCCTGTCCTGGGAGA Li-Fraumeni syndrome GACCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAG CTTTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGGTCTCTCC 322 CAGGACAGGCACAAACAC G CACCTCAAAGCTGTTCCGTCCCA GTAGATTACCACTACTCAGGATAGGAAAAGAGAAGCA TTGAGGTG C GTGTTTGT 323 ACAAACAC G CACCTCAA 324 TGT-TAT CTTTTCCTATCCTGAGTAGTGGTAATCTACTGGGACGGAACA 325 Cys-275 to Tyr GCTTTGAGGTGCGTGTTT G TGCCTGTCCTGGGAGAGACCGG Li-Fraumeni syndrome CGCACAGAGGAAGAGAATCTCCGCAAGAAAGGGGAGCC GGCTCCCCTTTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGG 326 TCTCTCCCAGGACAGGCA C AAACACGCACCTCAAAGCTGTTC CGTCCCAGTAGATTACCACTACTCAGGATAGGAAAAG GCGTGTTT G TGCCTGTC 327 GACAGGCA C AAACACGC 328 CCT-CTT TCCTGAGTAGTGGTAATCTACTGGGACGGAACAGCTTTGAGG 329 Pro-278 to Leu TGCGTGTTTGTGCCTGTC C TGGGAGAGACCGGCGCACAGAG Breast cancer GAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGA TCGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCTTCCTCT 330 GTGCGCCGGTCTCTCCCA G GACAGGCACAAACACGCACCTC AAAGCTGTTCCGTCCCAGTAGATTACCACTACTCAGGA TGCCTGTC C TGGGAGAG 331 CTCTCCCA G GACAGGCA 332 AGA-AAA GTAGTGGTAATCTACTGGGACGGAACAGCTTTGAGGTGCGTG 333 Arg-280 to Lys TTTGTGCCTGTCCTGGGA G AGACCGGCGCACAGAGGAAGAG Glioma AATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCTGCC GGCAGCTCGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCT 334 TCCTCTGTGCGCCGGTCT C TCCCAGGACAGGCACAAACACG CACCTCAAAGCTGTTCCGTCCCAGTAGATTACCACTAC TCCTGGGA G AGACCGGC 335 GCCGGTCT C TCCCAGGA 336 GAA-GCA GGAACAGCTTTGAGGTGCGTGWTTGTGCCTGTCCTGGGAGA 337 GTu-286 to Ala GACCGGCGCACAGAGGAAG A GAATCTCCGCAAGAATTAGGGGA Adrenocortical GCCTCACCACGAGCTGCCCCCAGGGAGCACTAAGCGAGG carcinoma CCTCGCTTAGTGCTCCCTGGGGGCAGCTCGTGGTGAGGCTC 338 CCCTTTCTTGCGGAGATTC T CTTCCTCTGTGCGCCGGTCTCT CCCAGGACAGGCACAAACACGCACCTCAAAGCTGTTCC AGAGGAAG A GAATCTCC 339 GGAGATTC T CTTCCTCT 340 CGA-CCA AAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCTG 341 Arg-306 to Pro CCCCCAGGGAGCACTAAGC G AGGTAAGCAAGCAGGACAAGA Rhabdomyosarcoma AGCGGTGGAGGAGACCAAGGGTGCAGTTATGCCTCAGAT ATCTGAGGCATAACTGCACCCTTGGTCTCCTCCACCGCTTCT 342 TGTCCTGCTTGCTTACCT C GCTTAGTGCTCCCTGGGGGCAGC TCGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCTT CACTAAGC G AGGTAAGC 343 GCTTACCT C GCTTAGTG 344 gCGA-TGA GAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCT 345 Arg-306 to Term GCCCCCAGGGAGCACTAAG C GAGGTAAGCAAGCAGGACAAG Li-Fraumeni syndrome AAGCGGTGGAGGAGACCAAGGGTGCAGTTATGCCTCAGA TCTGAGGCATAACTGCACCCTTGGTCTCCTCCACCGCTTCTT 346 GTCCTGCTTGCTTACCTC G CTTAGTGCTCCCTGGGGGCAGCT CGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCTTC GCACTAAG C GAGGTAAG 347 CTTACCTC G CTTAGTGC 348 gCGC-TGC GGTACTGTGAATATACTTACTTCTCCCCCTCCTCTGTTGCTGC 349 Arg-337 to Cys AGATCCGTGGGCGTGAG C GCTTCGAGATGTTCCGAGAGCTG Osteosarcoma AATGAGGCCTTGGAACTCAAGGATGCCCAGGCTGGGA TCCCAGCCTGGGCATCCTTGAGTTCCAAGGCCTCATTCAGCT 350 CTCGGAACATCTCGAAG C GCTCACGCCCACGGATCTGCAGC AACAGAGGAGGGGGAGAAGTAAGTATATTCACAGTACC GGCGTGAG C GCTTCGAG 351 CTCGAAGC G CTCACGCC 352 CTG-CCG CTCTCCCCCTCCTCTGTTGCTGCAGATCCGTGGGCGTGAGCGC 353 Leu-344 to Pro TTCGAGATGTTCCGAGAGC T GAATGAGGCCTTGGAACTCAAG Li-Fraumeni syndrome GATGCCCAGGCTGGGAAGGAGCCAGGGGGGAGCAGGGC GCCCTGCTCCCCCCTGGCTCCTTCCCAGCCTGGGCATCCTT 354 GAGTTCCAAGGCCTCATTC A GCTCTCGGAACATCTCGAAGCG CTCACGCCCACGGATCTGCAGCAACAGAGGAGGGGGAG CCGAGAGC T GAATGAGG 355 CCTCATTC A GCTCTCGG 356

EXAMPLE 6 Beta Globin

Hemoglobin, the major protein in the red blood cell, binds oxygen reversibly and is responsible for the cells' capacity to transport oxygen to the tissues. In adults, the major hemoglobin is hemoglobin A, a tetrameric protein consisting of two identical alpha globin chains and two beta globin chains. Disorders involving hemoglobin are among the most common genetic disorders worldwide, with approximately 5% of the world's population being carriers for clinically important hemoglobin mutations. Approximately 300,000 severely affected homozygotes or compound heterozygotes are born each year.

Mutation of the glutamic acid at position 7 in beta globin to valine causes sickle cell anemia, the clinical manifestations of which are well known. Mutations that cause absence of beta chain cause beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. For clinical purposes, beta-thalassemia is divided into thalassemia major (transfusion dependent), thalassemia intermedia (of intermediate severity), and thalassemia minor (asymptomatic). Patients with thalassemia major present in the first year of life with severe anemia; they are unable to maintain a hemoglobin level about 5 gm/dl.

The beta-thalassemias were among the first human genetic diseases to be examined by means of recombinant DNA analysis. Baysal et al., Hemoglobin 19(3-4):213-36 (1995) and others provide a compendium of mutations that result in beta-thalassemia.

Hemoglobin disorders were among the first to be considered for gene therapy. Transcriptional silencing of genes transferred into hematopoietic stem cells, however, poses one of the most significant challenges to its success. If the transferred gene is not completely silenced, a progressive decline in gene expression is often observed. Position effect variegation (PEV) and silencing mechanisms may act on a transferred globin gene residing in chromatin outside of the normal globin locus during the important terminal phases of erythroblast development when globin transcripts normally accumulate rapidly despite heterochromatization and shutdown of the rest of the genome. The attached table discloses the correcting oligonucleotide base sequences for the beta globin oligonucleotides of the invention.

TABLE 12 Beta Globin Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Sickle Cell Anemia TCTGACACAACTGTGTTCACTAGCAACCTCAAACAGACACCA 357 GLU-7-VAL TGGTGCACCTGACTCCTG A GGAGAAGTCTGCCGTTACTGCC GAG to GTG CTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGA TCACCACCAACTTCATCCACGTTCACCTTGCCCCACAGGGCA 358 GTAACGGCAGACTTCTCC T CAGGAGTCAGGTGCACCATGGT GTCTGTTTGAGGTTGCTAGTGAACACAGTTGTGTCAGA GACTCCTG A GGAGAAGT 359 ACTTCTCC T CAGGAGTC 360 Thalassaemia Beta CTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCA 361 MET-0-ARG ACCTCAAACAGACACCA T GGTGCACCTGACTCCTGAGGAGA ATG to AGG AGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGT ACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTC 362 CTCAGGAGTCAGGTGCACC A TGGTGTCTGTTTGAGGTTGCT AGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAG AGACACCA T GGTGCACC 363 GGTGCACC A TGGTGTCT 364 Thalassaemia Beta TATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCAA 365 MET-0-ILE CCTCAAACAGACACCAT G GTGCACCTGACTCCTGAGGAGAA ATG to ATA GTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTG CACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCT 366 CCTCAGGAGTCAGGTGCAC C ATGGTGTCTGTTTGAGGTTGC TAGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATA GACACCAT G GTGCACCT 367 AGGTGCAC C ATGGTGTC 368 Thalassaemia Beta TATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCAA 369 MET-0-ILE CCTCAAACAGACACCAT G GTGCACCTGACTCCTGAGGAGAAT ATG to ATT GTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTG CACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCT 370 CCTCAGGAGTCAGGTGCAC C ATGGTGTCTGTTTGAGGTTGC TAGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATA GACACCAT G GTGCACCT 371 AGGTGCAC C ATGGTGTC 372 Thalassaemia Beta CTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCA 373 MET-0-LYS ACCTCAAACAGACACCA T GGTGCACCTGACTCCTGAGGAGA ATG to AAG AGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGT ACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTC 374 CTCAGGAGTCAGGTGCACC A TGGTGTCTGTTTGAGGTTGCT AGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAG AGACACCA T GGTGCACC 375 GGTGCACC A TGGTGTCT 376 Thalassaemia Beta CTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCA 377 MET-0-THR ACCTCAAACAGACACCA T GGTGCACCTGACTCCTGAGGAGA ATG to ACG AGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGT ACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTC 378 CTCAGGAGTCAGGTGCACC A TGGTGTCTGTTTGAGGTTGCT AGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAG AGACACCA T GGTGCACC 379 GGTGCACC A TGGTGTCT 380 Thalassaemia Beta TCTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGC 381 MET-0-VAL AACCTCAAACAGACACC A TGGTGCACCTGACTCCTGAGGAG ATG to GTG AAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACG CGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTCC 382 TCAGGAGTCAGGTGCACCA T GGTGTCTGTTTGAGGTTGCTAG TGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAGA CAGACACC A TGGTGCAC 383 GTGCACCA T GGTGTCTG 384 Thalassaemia Beta TCAAACAGACACCATGGTGCACCTGACTCCTGAGGAGAAGT 385 TRP-16-Term CTGCCGTTACTGCCCTGTG G GGCAAGGTGAACGTGGATGAA TGG to TGA GTTGGTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTTA TAACCTTGATACCAACCTGCCCAGGGCCTCACCACCAACTTC 386 ATCCACGTTCACCTTGCC C CACAGGGCAGTAACGGCAGACT TCTCCTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGA GCCCTGTG G GGCAAGGT 387 ACCTTGCC C CACAGGGC 388 Thalassaemia Beta CTCAAACAGACACCATGGTGCACCTGACTCCTGAGGAGAAG 389 TRP-16-Term TCTGCCGTTACTGCCCTGT G GGGCAAGGTGAACGTGGATGA TGG to TAG AGTTGGTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTT AACCTTGATACCAACCTGCCCAGGGCCTCACCACCAACTTCA 390 TCCACGTTCACCTTGCCC C ACAGGGCAGTAACGGCAGACTT CTCCTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGAG TGCCCTGT G GGGCAAGG 391 CCTTGCCC C ACAGGGCA 392 Thalassaemia Beta ACAGACACCATGGTGCACCTGACTCCTGAGGAGAAGTCTGC 393 LYS-18-Term CGTTACTGCCCTGTGGGGC A AGGTGAACGTGGATGAAGTTG AAG to TAG GTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTTACAAG CTTGTAACCTTGATACCAACCTGCCCAGGGCCTCACCACCAA 394 CTTCATCCACGTTCACCT T GCCCCACAGGGCAGTAACGGCA GACTTCTCCTCAGGAGTCAGGTGCACCATGGTGTCTGT TGTGGGGC A AGGTGAAC 395 GTTCACCT T GCCCCACA 396 Thalassaemia Beta CCATGGTGCACCTGACTCGTGAGGAGAAGTCTGCCGTTACT 397 ASN-20-SER GCCCTGTGGGGCAAGGTGA A CGTGGATGAAGTTGGTGGTGA AAC to AGC GGCCCTGGGCAGGTTGGTATCAAGGTTACAAGACAGGTT AACCTGTCTTGTAACCTTGATACCAACCTGCCCAGGGCCTCA 398 CCACCAACTTCATCCACG T TCACCTTGCCCCACAGGGCAGTA ACGGCAGACTTCTCCTCAGGAGTCAGGTGCACCATGG CAAGGTGA A CGTGGATG 399 CATCCACG T TCACCTTG 400 Thalassaemia Beta ACCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGG 401 GLU-23-ALA GGCAAGGTGAACGTGGATG A AGTTGGTGGTGAGGCCCTGG GAA to GCA GCAGGTTGGTATCAAGGTTACAAGACAGGTTTAAGGAGAC GTCTCCTTAAACCTGTCTTGTAACCTTGATACCAACCTGCCC 402 AGGGCCTCACCACCAACT T CATCCACGTTCACCTTGCCCCAC AGGGCAGTAACGGCAGACTTCTCCTCAGGAGTCAGGT CGTGGATG A AGTTGGTG 403 CACCAACT T CATCCACG 404 Thalassaemia Beta CACCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTG 405 GLU-23-term GGGCAAGGTGAACGTGGAT G AAGTTGGTGGTGAGGCCCTG GAA to TAA GGCAGGTTGGTATCAAGGTTACAAGACAGGTTTAAGGAGA TCTCCTTAAACCTGTCTTGTAACCTTGATACCAACCTGCCCA 406 GGGCCTCACCACCAACTT C ATCCACGTTCACCTTGCCCCACA GGGCAGTAACGGCAGACTTCTCCTCAGGAGTCAGGTG ACGTGGAT G AAGTTGGT 407 ACCAACTT C ATCCACGT 408 Thalassaemia Beta GAGGAGAAGACTGCTGTCAATGCCCTGTGGGGCAAAGTGAA 409 GLU-27-LYS CGTGGATGCAGTTGGTGGT G AGGCCCTGGGCAGGTTGGTAT GAG to AAG CAAGGTTATAAGAGAGGCTCAAGGAGGCAAATGGAAACT AGTTTCCATTTGCCTCCTTGAGCCTCTCTTATAACCTTGATAC 410 CAACCTGCCCAGGGCCT C ACCACCAACTGCATCCACGTTCA CTTTGCCCCACAGGGCATTGACAGCAGTCTTCTCCTC TTGGTGGT G AGGCCCTG 411 CAGGGCCT C ACCACCAA 412 Thalassaemia Beta GAGGAGAAGACTGCTGTCAATGCCCTGTGGGGCAAAGTGAA 413 GLU-27-Term CGTGGATGCAGTTGGTGGT G AGGCCCTGGGCAGGTTGGTAT GAG to TAG CAAGGTTATAAGAGAGGCTCAAGGAGGCAAATGGAAACT AGTTTCCATTTGCCTCCTTGAGCCTCTCTTATAACCTTGATAC 414 CAACCTGCCCAGGGCCT C ACCACCAACTGCATCCACGTTCA CTTTGCCCCACAGGGCATTGACAGCAGTCTTCTCCTC TTGGTGGT G AGGCCCTG 415 CAGGGCCT C ACCACCAA 416 Thalassaemia Beta GAGAAGACTGCTGTCAATGCCCTGTGGGGCAAAGTGAACGT 417 ALA-28-SER GGATGCAGTTGGTGGTGAG G CCCTGGGCAGGTTGGTATCAA GCC to TCC GGTTATAAGAGAGGCTCAAGGAGGCAAATGGAAACTGGG CCCAGTTTCCATTTGCCTCCTTGAGCCTCTCTTATAACCTTGA 418 TACCAACCTGCCCAGGG C CTCACCACCAACTGCATCCACGT TCACTTTGCCCCACAGGGCATTGACAGCAGTCTTCTC GTGGTGAG G CCCTGGGC 419 GCCCAGGG C CTCACCAC 420 Thalassaemia Beta CTGTCAATGCCCTGTGGGGCAAAGTGAACGTGGATGCAGTT 421 ARG-31-THR GGTGGTGAGGCCCTGGGCA G GTTGGTATGAAGGTTATAAGA AGG to ACG GAGGCTCAAGGAGGCAAATGGAAACTGGGCATGTGTAGA TCTACACATGCCCAGTTTCCATTTGCCTCCTTGAGCCTCTCTT 422 ATAACCTTGATACCAAC C TGCCCAGGGCCTCACCACCAACTG CATCCACGTTCACTTTGCCCCACAGGGCATTGACAG CCTGGGCA G GTTGGTAT 423 ATACCAAC C TGCCCAGG 424 Thalassaemia Beta TGGGTTTCTGATAGGCACTGACTCTCTGTCCCTTGGGCTGTT 425 Leu-33-GLN TTCCTACCCTCAGATTAC T GGTGGTCTACCCTTGGACCCAGA CTG to CAG GGTTCTTTGAGTCCTTTGGGGATCTGTCCTCTCCTGA TCAGGAGAGGAGAGATCCCCAAAGGACTCAAAGAACCTCTG 426 GGTCCAAGGGTAGACCACC A GTAATCTGAGGGTAGGAAAAC AGCCCAAGGGACAGAGAGTCAGTGCCTATCAGAAACCCA CAGATTAC T GGTGGTCT 427 AGACCACC A GTAATCTG 428 Thalassaemia Beta ATAGGCACTGACTCTCTGTCCCTTGGGCTGTTTTCCTACCCT 429 TYR-36-Term CAGATTACTGGTGGTCTA C CCTTGGACCCAGAGGTTCTTTGA TAC to TAA GTCCTTTGGGGATCTGTCCTCTCCTGATGCTGTTATG CATAACAGCATCAGGAGAGGACAGATCCCCAAAGGACTCAAA 430 GAACCTCTGGGTCCAAGG G TAGACCACCAGTAATCTGAGGG TAGGAAAACAGCCCAAGGGACAGAGAGTCAGTGCCTAT GTGGTCTA C CCTTGGAC 431 GTCCAAGG G TAGACCAC 432 Thalassaemia Beta ACTGACTCTCTGTCCCTTGGGCTGTTTTCCTACCCTCAGATT 433 TRP-38-Term ACTGGTGGTCTACCCGTTG G ACCCAGAGGTTCTTTGAGTCCTT TGG to TGA TGGGGATCTGTCCTCTCCTGATGCTGTTATGGGCAAC GTTGCCCATAACAGCATCAGGAGAGGACAGATCCCCAAAGG 434 ACTCAAAGAACCTCTGGGT C CAAGGGTAGACCACCAGTAATC TGAGGGTAGGAAAACAGCCCAAGGGACAGAGAGTCAGT TACCCTTG G ACCCAGAG 435 CTCTGGGT C CAAGGGTA 436 Thalassaemia Beta CACTGACTCTCTGTCCCTTGGGCTGTTTTCCTACCCTCAGAT 437 TRP-38-Term TACTGGTGGTCTACCCTT G GACCCAGAGGTTCTTGAGTCCT TGG to TAG TTGGGGATCTGTCCTCTCCTGATGCTGTTATGGGCAA TTGCCCATAACAGCATCAGGAGAGGACAGATCCCCAAAGGA 438 CTCAAAGAACCTCTGGGTC C AAGGGTAGACCACCAGTAATCT GAGGGTAGGAAAACAGCCCAAGGGACAGAGAGTCAGTG CTACCCTT G GACCCAGA 439 TCTGGGTC C AAGGGTAG 440 Thalassaemia Beta ACTCTCTGTCCCTTGGGCTGTTTTCCTACCCTCAGATTACTG 441 GLN-40-Term GTGGTCTACCCTTGGACC C AGAGGTTCTTTGAGTCCTTTGGG CAG-TAG GATCTGTCCTCTCCTGATGCTGTTATGGGCAACCCTA TAGGGTTGCCCATAACAGCATCAGGAGAGGACAGATCCCCA 442 AAGGACTCAAAGAACCTCT G GGTCCAAGGGTAGACCACCAG TAATCTGAGGGTAGGAAAACAGCCCAAGGGAGAGAGAGT CTTGGACC C AGAGGTTC 443 GAACCTCT G GGTCCAAG 444 Thalassaemia Beta TTGGGCTGTTTTCCTACCCTCAGATTACTGGTGGTCTACCCT 445 GLU-44-Term TGGACCCAGAGGTTCTTT G AGTCCTTTGGGGATCTGTCCTCT GAG to TAG CCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTC GAGCCTTCACCTTAGGGTTGCCCATAACAGCATCAGGAGAG 446 GACAGATCCCCAAAGGACT C AAAGAACCTGTGGGTCCAAGG GTAGACCACCAGTAATCTGAGGGTAGGAAAACAGCCCAA GGTTCTTT G AGTCCTTT 447 AAAGGACT C AAAGAACC 448 Thalassaemia Beta TTCTTTGAGTCCTTTGGGGATCTGTCCTCTCCTGATGCTGTTA 449 LYS-62-Term TGGGCAACCCTAAGGTG A AGGCTCATGGCAAGAAGGTGCTA AAG to TAG GGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACC GGTTGTCCAGGTGAGCCAGGCCATCACTAAAGGCACCTAGC 450 ACCTTCTTGCCATGAGCCT T CACCTTAGGGTTGCCCATAACA GCATCAGGAGAGGACAGATCCCCAAAGGACTCAAAGAA CTAAGGTG A AGGCTCAT 451 ATGAGCCT T CACCTTAG 452 Thalassaemia Beta TGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGA 453 SER-73-ARG AGGTGCTAGGTGCCTTTAG T GATGGCCTGGCTCACCTGGAC AGT to AGA AACCTCAAGGGCACTTTTTCTCAGCTGAGTGAGCTGCAC GTGCAGCTCACTCAGCTGAGAAAAAGTGCCCTTGAGGTTGTC 454 CAGGTGAGCCAGGCCATC A CTAAAGGCACCTAGCACCTTCT TGCCATGAGCCTTCACCTTAGGGTTGCCCATAACAGCA GCCTTTAG T GATGGCCT 455 AGGCCATC A CTAAAGGC 456 Haemolylic Anaemia TTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAGGTG 457 GLY-75-VAL CTAGGTGCCTTTTAGTGATG G CCTGGCTCACCTGGACAACCT GGC to GTC CAAGGGCACTTTTTCTCAGCTGAGTGAGCTGCACTGTGA TCACAGTGCAGCTCACTCAGCTGAGAAAAAGTGCCCTTGAG 458 GTTGTCCAGGTGAGCCAGG C CATCACTAAAGGCACCTAGCA CCTTCTTGCCATGAGCCTTCACCTTAGGGTTGCCCATAA TAGTGATG G CCTGGCTC 459 GAGCCAGG C CATCACTA 460 Thalassaemia Beta GCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGG 461 GLU-91-Term CACCTTTGCCACACTGAGT G AGCTGCACTGTGACAAGCTGC GAG to TAG ACGTGGATCCTGAGAACTTCAGGGTGAGTCTATGGGACC GGTCCCATAGACTCACCCTGAAGTTCTCAGGATCCACGTGCA 462 GCTTGTCACAGTGCAGCT C ACTCAGTGTGGCAAAGGTGCCC TTGAGGTTGTCCAGGTGAGCCAGGCCATCACTAAAGGC CACTGAGT G AGCTGCAC 463 GTGCAGCT C ACTCAGTG 464 Thalassaemia Beta CTGGACAACCTCAAGGGCACTTTTTCTCAGCTGAGTGAGCTG 465 VAL-99-MET CACTGTGACAAGCTGCAC G TGGATCCTGAGAACTTCAGGGT GTG to ATG GAGTCCAGGAGATGCTTCACTTTTCTCTTTTTACTTTC GAAAGTAAAAAGAGAAAAGTGAAGCATCTCCTGGACTCACCC 466 TGAAGTTCTCAGGATCCA C GTGCAGCTTGTCACAGTGCAGCT CACTCAGCTGAGAAAAAGTGCCCTTGAGGTTGTCCAG AGCTGCAC G TGGATCCT 467 AGGATCCA C GTGCAGCT 468 Thalassaemia Beta CCCTTTTGCTAATCATGTTCATACCTCTTATCTTCCTCCCACA 469 LEU-111-PRO GCTCCTGGGCAACGTGC T GGTCTGTGTGCTGGCCCATCACT CTG-CCG TTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTA TAGGCAGCCTGCACTGGTGGGGTGAATTCTTTGCCAAAGTG 470 ATGGGCCAGCACACAGACC A GCACGTTGCCCAGGAGCTGTG GGAGGAAGATAAGAGGTATGAACATGATTAGCAAAAGGG CAACGTGC T GGTCTGTG 471 CACAGACC A GCACGTTG 472 Thalassaemia Beta GCTAATCATGTTCATACCTCTTATCTTCCTCCCACAGCTCCTG 473 CYS-113-Term GGCAACGTGCTGGTCTG T GTGCTGGCCCATCACTTTGGCAA TGT to TGA AGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAA TTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCTTTGCC 474 AAAGTGATGGGCCAGCAC A CAGACCAGCACGTTGCCCAGGA GCTGTGGGAGGAAGATAAGAGGTATGAACATGATTAGC CTGGTCTG T GTGCTGGC 475 GCCAGCAC A CAGACCAG 476 Thalassaemia Beta TCATGTTCATACCTCTTATCTTCCTCCCACAGCTCCTGGGCA 477 LEU-115-PRO ACGTGCTGGTCTGTGTGC T GGCCCATCACTTTGGCAAAGAAT CTG to CCG TCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGT ACCACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCT 478 TTGCCAAAGTGATGGGCC A GCACACAGACCAGCACGTTGCC CAGGAGCTGTGGGAGGAAGATAAGAGGTATGAACATGA CTGTGTGC T GGCCCATC 479 GATGGGCC A GCACACAG 480 Thalassaemia Beta TGTTCATACCTCTTATCTTCCTCCCACAGCTCCTGGGCAACG 481 ALA-116-ASP TGCTGGTCTGTGTGCTGG C CCATCACTTTGGCAAAGAATTCA GCC to GAC CCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGC GCCACCACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAA 482 TTCTTTGCCAAAGTGATGG G CCAGCACACAGACCAGCACGTT GCCCAGGAGCTGTGGGAGGAAGATAAGAGGTATGAACA TGTGCTGG C CCATCACT 483 AGTGATGG G CCAGCACA 484 Thalassaemia Beta TTCCTCCCACAGCTCCTGGGCAACGTGCTGGTCTGTGTGCT 485 GLU-122-Term GGCCCATCACTTTGGCAAA G AATTCACCCCACCAGTGCAGG GAA to TAA CTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCC GGGCATTAGCCACACCAGCCACCACTTTCTGATAGGCAGCC 486 TGCACTGGTGGGGTGAATT C TTTGCCAAAGTGATGGGCCAG CACACAGACCAGCACGTTGCCCAGGAGCTGTGGGAGGAA TTGGCAAA G AATTCACC 487 GGTGAATT C TTTGCCAA 488 Thalassaemia Beta GCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAA 489 GLN-128-PRO GAATTCACCCCACCAGTGC A GGCTGCCTATCAGAAAGTGGT CAG to CCG GGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTA TAGTGATACTTGTGGGCCAGGGCATTAGCCACACCAGCCAC 490 CACTTTCTGATAGGCAGCC T GCACTGGTGGGGTGAATTCTTT GCCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGC ACCAGTGC A GGCTGCCT 491 AGGCAGCC T GCACTGGT 492 Thalassaemia Beta GGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAA 493 GLN-128-Term AGAATTCACCCCACCAGTG C AGGCTGCCTATCAGAAAGTGGT CAG to TAG GGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACT AGTGATACTTGTGGGCCAGGGCATTAGCCACACCAGCCACC 494 ACTTTCTGATAGGCAGCCT G CACTGGTGGGGTGAATTCTTTG CCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGCC CACCAGTG C AGGCTGCC 495 GGCAGCCT G CACTGGTG 496 Thalassaemia Beta GTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCA 497 GLN-132-LYS CCAGTGCAGGCTGCCTAT C AGAAAGTGGTGGCTGGTGTGGC CAG to AAG TAATGCCCTGGCCCACAAGTATCACTAAGCTCGCTTTC GAAAGCGAGCTTAGTGATACTTGTGGGCCAGGGCATTAGCC 498 ACACCAGCCACCACTTTCT G ATAGGCAGCCTGCACTGGTGG GGTGAATTCTTTGCCAAAGTGATGGGCCAGCACACAGAC CTGCCTAT C AGAAAGTG 499 CACTTTCT G ATAGGCAG 500

EXAMPLE 7 Retinoblastoma

Retinoblastoma (RB) is an embryonic neoplasm of retinal origin. It almost always presents in early childhood and is often bilateral. The risk of osteogenic sarcoma is increased 500-fold in bilateral retinoblastoma patients, the bone malignancy being at sites removed from those exposed to radiation treatment of the eye tumor.

The retinoblastoma susceptibility gene (pRB; pRb) plays a pivotal role in the regulation of the cell cycle. pRB restrains cell cycle progression by maintaining a checkpoint in late G₁ that controls commitment of cells to enter S phase. The critical role that pRB plays in cell cycle regulation explains its status as archetypal tumor suppressor: loss of pRB function results in an inability to maintain control of the G₁ checkpoint; unchecked progression through the cell cycle is, in turn, a hallmark of neoplasia.

Blanquet et al., Hum. Molec. Genet. 4: 383-388 (1995) performed a mutation survey of the RB1 gene in 232 patients with hereditary or nonhereditary retinoblastoma. They systematically explored all 27 exons and flanking sequences, as well as the promoter. All types of point mutations were represented and found to be unequally distributed along the RB1 gene sequence. In the population studied, exons 3, 8, 18, and 19 were preferentially altered. The attached table discloses the correcting oligonucleotide base sequences for the retinoblastoma oligonucleotides of the invention.

TABLE 13 pRB Mutations and Genome-Correcting Oligos Clinical Phenotype SEQ ID Mutation Correcting Oligos NO: Retinoblastoma AATATTTGATCTTTATTTTTTGTTCCCAGGGAGGTTATATTCAA 501 Trp99Term AAGAAAAAGGAACTGT G GGGAATCTGTATCTTTATTGCAGCA TGG-TAG GTTGACCTAGATGAGATGTCGTTCACTTTTACTGA TCAGTAAAAGTGAACGACATCTCATCTAGGTCAACTGCTGCA 502 ATAAAGATACAGATTCCC C ACAGTTCCTTTTTCTTTTGAAIATA ACCTCCCTGGGAACAAAAAATAAAGATCAAATATT GGAACTGT G GGGAATCT 503 AGATTCCC C ACAGTTCC 504 Retinoblastoma ATTTACTTTTTTCTATTCTTTCCTTTGTAGTGTCCATAAATTCTT 505 Glu137Asp TAACTTACTAAAAGA A ATTGATACCAGTACCAAAGTTGATAAT GAA-GAT GCTATGTCAAGACTGTTGAAGAAGTATGAIGTA TACATCATACTTCTTCAACAGTCTTGACATAGCATTATCAACTT 506 TGGTACTGGTATCAAT T TCTTTTAGTAAGTTAAAGAATTTATGG ACACTACAAAGGAAAGAATAGAAAAAAGTAAAT CTAAAAGA A ATTGATAC 507 GTATCAAT T TCTTTTAG 508 Retinoblastoma TGATTTACTTTTTTTCTATTCTTTCCTTTGTAGTGTCCATAAATT 509 Glu137Term CTTTAACTTACTAAAA G AAATTGATACCAGTACCAAAGTTGAT GAA-TAA AATGCTATGTCAAGACTGTTGAAGAAGTATGATG CATCATACTTCTTCAACAGTCTTGACATAGCATTATCAACTTT 510 GGTACTGGTATCAATTT C TTTTAGTAAGTTAAAGAATTTATGG ACACTACAAAGGAAAGAATAGAAAAAAGTAAATCA TACTAAAA G AAATTGAT 511 ATCAATTT C TTTTAGTA 512 Retinoblastoma AAAATGTTAAAAAGTCATAATGTTTTTCTTTTCAGGACATGTGA 513 Gln176Term ACTTATATATTTGACA C AACCCAGCAGTTCGTAAGTAGTTCAC CAA-TAA AGAATGTTATTTTTCACTTAAAAAAAAAGATTTT AAAATCTTTTTTTTTAAGTGAAAAATAACATTCTGTGAACTACT 514 TACGAACTGCTGGGTT G TGTCAAATATATAAGTTCACATGTCC TGAAAAGAAAAACATTATGACTTTTTAACATTTT ATTTGACA C AACCCAGC 515 GCTGGGTT G TGTCAAAT 516 Relinoblastoma TGATACATTTTTCCTGTTTTTTTTCTGCTTTCTATTTGTTTAATA 517 lle185Thr GGATATCTACTGAAA T AAATTCTGCATTGGTGCTAAAAGTTTC ATA-ACA TTGGATCACATTTTTATTAGCTAAAGGTAAGTT AACTTACCTTTAGCTAATAAAAATGTGATCCAAGAAACTTTTA 518 GCACCAATGCAGAATTT A TTTCAGTAGATATCCTATTAAACAA ATAGAAAGCAGAAAAAAAACAGGAAAAATGTATCA TACTGAAA T AAATTCTG 519 CAGAATTT A TTTCAGTA 520 Retinoblastoma AAAGATCTGAATCTCTAACTTTCTTTAAAAATGTACATTTTTTT 521 Gln207Term TTCAGGGGAAGTATTA C AAATGGAAGATGATCTGGTGATTTC CAA-TAA ATTTCAGTTAATGCTATGTGTCCTTGACTATTTTA TAAAATAGTCAAGGACACATAGCATTAACTGAAATGAAATCAC 522 CAGATCATCTTCCATTT G TAATACTTCCCCTGAAAAAAAAAATG TACATTTTTAAAGAAAGTTAGAGATTCAGATCTTT AAGTATTA C AAATGGAA 523 TTCCATTT G TAATACTT 524 Retinoblastoma GTTCTTATCTAATTTACCACTTTTACAGAAACAGCTGTTATACC 525 Arg251Term CATTAATGGTTCACCT C GAACACCCAGGCGAGGTCAGAACA CGA to TGA GGAGTGCACGGATAGCAAAACAACTAGAAAATGATA TATCATTTTCTAGTTGTTTTGCTATCCGTGCACTCCTGTTCTG 526 ACCTCGCCTGGGTGTTC G AGGTGAACCATTAATGGGTATAAC AGCTGTTTCTGTAAAAGTGGTAAATTAGATAAGAAC GTTCACCT C GAACACCC 527 GGGTGTTC G AGGTGAAC 528 Retinoblastoma TTTACCACTTTTACAGAAACAGCTGTTATACCCATTAATGGTT 529 Arg255Term CACCTCGAACACCCAGG C GAGGTCAGAACAGGAGTGCACG CGA to TGA GATAGCAAAACAACTAGAAAATGATACAAGAATTATTG CAATAATTCTTGTATCATTTTCTAGTTGTTTTGCTATCCGTGCA 530 CTCCTGTTCTGACCTC G CCTGGGTGTTCGAGGTGAACCATTA ATGGGTATAACAGCTGTTTCTGTAAAAGTGGTAAA CACCCAGG C GAGGTCAG 531 CTGACCTC G CCTGGGTG 532 Retinoblastoma ATTAATGGTTCACCTCGAACACCCAGGCGAGGTCAGAACAG 533 Gln266Term GAGTGCACGGATAGCAAAA C AACTAGAAAATGATACAAGAAT CAA to TAA TATTGAAGTTCTCTGTAAAGAACATGAATGTAATATAG CTATATTACATTCATGTTCTTTACAGAGAACTTCAATAATTCTT 534 GTATCATTTTCTAGTT G TTTTGCTATCCGTGCACTCCTGTTCT GACCTCGCCTGGGTGTTCGAGGTGAACCATTAAT TAGCAAAA C AACTAGAA 535 TTCTAGTT G TTTTGCTA 536 Retinoblastoma TGACATGTAAAGGATAATTGTCAGTGACTTTTTTCTTTCAAGG 537 Arg320Term TTGAAAATCTTTCTAAA C GATACGAAGAAATTTATCTTAAAAAT CGA to TGA AAAGATCTAGATGCAAGATTATTTTTGGATCATG CATGATCCAAAAATAATCTTGCATCTAGATCTTTATTTTTAAGA 538 TAAATTTCTTCGTATC G TTTAGAAAGATTTTCAACCTTGAAAGA AAAAAGTCACTGACAATTATCCTTTACATGTCA TTTCTAAA C GATACGAA 539 TTCGTATC G TTTAGAAA 540 Retinoblastoma ACAAATTGTAAATTTTCAGTATGAAGACTTGACTTCACTTATTGTT 541 Gln354Term ATTTAGTTTTGAAACA C AGAGAACACCACGAAAAAGTAACCTT CAG to TAG GATGAAGAGGTGAATGTAATTCCTCCACACACTC GAGTGTGTGGAGGAATTACATTCACCTCTTCATCAAGGTTAC 542 TTTTTCGTGGTGTTCTCT G TGTTTCAAAACTAAATAACAATAA GTGAAGTCATTCACATACTGAAAATTTACAATTTGT TTGAAACA C AGAGAACA 543 TGTTCTCT G TGTTTCAA 544 Retinoblastoma TTTTCAGTATGIGAATGACTTCACTTATTGTTATTTAGTTTTGA 545 Arg358Gly AACACAGAGAACACCA C GAAAAAGTAACCTTGATGAAGAGGT CGA to GGA GAATGTAATTCCTCCACACACTCCAGTTAGGTATG CATACCTAACTGGAGTGTGTGGAGGAATTACATTCACCTCTT 546 CATCAAGGTTACTTTTTC G TGGTGTTCTCTGTGTTTCAAAACT AAATAACAATAAGTGAAGTCATTCACATACTGAAAA GAACACCA C GAAAAAGT 547 ACTTTTTC G TGGTGTTC 548 Retinoblastoma TTTTCAGTATGTGAATGACTTCACTTATTGTTATTTATTTTTGA 549 Arg358Term AACACAGAGAACACCA C GAAAAAGTAACCTTGATGAAGAGGT CGA to TGA GAATGTAATTCCTCCACACACTCCAGTTAGGTATG CATACCTAACTGGAGTGTGTGGAGGAATTACATTCACCTCTT 550 CATCAAGGTTACTTTTTC G TGGTGTTCTCTGTGTTTCAAAACT AAATAACAATAAGTGAAGTCATTCACATACTGAAAA GAACACCA C GAAAAAGT 551 ACTTTTTC G TGGTGTTC 552 Retinoblastoma CTGTTATGAACACTATCCAACAATTAATGATGATTTTAAATTCA 553 Ser397Term GCAAGIGATCAACCTT C AGAAAATCTGATTTCCTATTTTAACG TCA to TAA TAAGCCATATATGAAACATTATTTATTGTAATAT ATATTACAATAAATAATGTTTCATATATGGCTTACGTTAAAATA 554 GGAAATCAGATTTTCT G AAGGTTGATCACTTGCTGAATTTAAA ATCATCATTAATTGTTGGATAGTGTTCATAACAG TCAACCTT C AGAAAATC 555 GATTTTCT G AAGGTTGA 556 Retinoblastoma TTTCATAATTGTGATTTTCTAAAATAGCAGGCTCTTATTTTTCT 557 Arg445Term TTTTGTTTGTTTGTAG C GATACAAACTTGGAGTTCGCTTGTAT CGA to TGA TACCGAGTAATGGAATCCATGCTTAAATCAGTAA TTACTGATTTAAGCATGGATTCCATTACTCGGTAATACAAGCG 558 AACTCCAAGTTTGTATC G CTACAAACAAACAAAAAGAAAAATA AGAGCCTGCTATTTTAGAAAATCACAATTATGAAA GTTTGTAG C GATACAAA 559 TTTGTATC G CTACAAAC 560 Retinoblastoma GCTCTTATTTTTCTTTTTGTTTGTTTGTAGCGATACAAACTTGG 561 Arg455Term AGTTCGCTTGTATTAC C GAGTAATGGAATCCATGCTTAAATCA CGA to TGA GTAAGTAAAAACAATATAAAAAAATTTCAGCCG CGGCTGAAATTTTTTTATATTGTTTTTAACTTACTGATTTAAGC 562 ATGGATTCCATTACTC G GTAATACAAGCGAACTCCAAGTTTGT ATCGCTACAAACAAACAAAAAGAAAAATAAGAGC TGTATTAC C GAGTAATG 563 CATTACTC G GTAATACA 564 Retinoblastoma ATCGAAAGTTTTATCAAAGCAGAAGGCAACTTGACAAGAGAA 565 Arg552Term ATGATAAAACATTTAGAA C GATGTGAACATCGAATCATGGAAT CGA to TGA CCCTTGCATGGCTCTCAGTAAGTAGCTAAATAATTG CAATTATTTAGCTACTTACTGAGAGCCATGCAAGGGATTCCAT 566 GATTCGATGTTCACATC G TTCTAAATGTTTTATCATTTCTCTTG TCAAGTTGCCTTCTGCTTTGATAAAACTTTCGAT ATTTAGAA C GATGTGAA 567 TTCACATC G TTCAAAT 568 Retinoblastoma AAGTTTTATCAAAGCAGAAGGCAACTTGACAAGAGAAATGATA 569 Cys553Term AAACATTTAGAACGATG T GAACATCGAATCATGGAATCCCTTG TGT to TGA CATGGCTCTCAGTAAGTAGCTAAATAATTGAAGAA TTCTTCAATTATTTAGCTACTTACTGAGAGCCATGCAAGGGAT 570 TCCATGATTCGATGTTC A CATCGTTCTAAATGTTTTATCATTTC TCTTGTCAAGTTGCCTTCTGCTTTGATAAAACTT GAACGATG T GAACATCG 571 CGATGTTC A CATCGTTC 572 Retinoblastoma AGTTTTATCAAAGCAGAAGGCAACTTGACAAGAGAAATGATAA 573 Glu554Term AACATTTAGAACGATGT G AACATCGAATCATGGAATCCCTTG GAA to TAA CATGGCTCTCAGTAAGTAGCTAAATAATTGAAGAAA TTTCTTCAATTATTTAGCTACTTACTGAGAGCCATGCAAGGGA 574 TTCCATGATTCGATGTT C ACATCGTTCTAAATGTTTTATCATTT CTCTTGTCAAGTTGCCTTCTGCTTTGATAAAACT AACGATGT G AACATCGA 575 TCGATGTT C ACATCGTT 576 Retinoblastoma TACCTGGGAAAATTATGCTTACTAATGTGGTTTTAATTTCATC 577 Ser567Leu ATGTTTCATATAGGATT C ACCTTTATTTGATCTTATTAAACAAT TCA to TTA CAAAGGACCGAGAAGGACCAACTGATCACCTTGA TCAAGGTGATCAGTTGGTCCTTCTCGGTCCTTTGATTGTTTAA 578 TAAGATCAAATAAAGGT G AATCCTATATGAAACATGATGAAAT TAAAACCACATTAGTAAGCATAATTTTCCCAGGTA ATAGGATT C ACCTTTAT 579 ATAAAGGT G AATCCTAT 580 Retinoblastoma AATGTGGTTTTAATTTCATCATGTTTFCATATAGGATTCACCTTT 581 Gln575Term ATTTGATCTTATTAAA C AATCAAAGGACCGAGAAGGACCAACT CAA to TAA GATCACCTTGAATCTGCTTGTCCTCTTAATCTTC GAAGATTAAGAGGACAAGCAGATTCAAGGTGATCAGTTGGTC 582 CTTCTCGGTCCTTTGATT G TTTAATAAGATCAAATAAAGGTGA ATCCTATATGAAACATGATGAAATTAAAACCACATT TTATTAAA C AATCAAAG 583 CTTTGATT G TTTAATAA 584 Retinoblastoma ATTTCATCATGTTTCATATAGGATTCACCTTTATTTGATCTTAT 585 Arg579Term TAAACAATCAAAGGAC C GAGAAGGACCAACTGATCACCTTGA CGA to TGA ATCTGCTTGTCCTCTTAATCTTCCTCTCCAGAATA TATTCTGGAGAGGAAGATTAAGAGGACAAGCAGATTCAAGGT 586 GATCAGTTGGTCCTTCTC G GTCCTTTGATTGTTTAATAAGATC AAATAAAGGTGAATCCTATATGAAACATGATGAAAT CAAAGGAC C GAGAAGGA 587 TCCTTCTC G GTCCTTTG 588 Retinoblastoma TCATCATGTTTCATATAGGATTCACCTTTATTTGATCTTATTAA 589 Glu580Term ACAATCAAAGGACCGA G AAGGACCAACTGATCACCTTGAATC GAA to TAA TGCTTGTCCTCTTAATCTTCCTCTCCAGAATAATC GATTATTCTGGAGAGGAAGATTAAGAGGACAAGCAGATTCAA 590 GGTGATCAGTTGGTCCTT C TCGGTCCTTTGATTGTTTAATAAG ATCAAATAAAGGTGAATCCTATATGAAACATGATGA AGGACCGA G AAGGACCA 591 TGGTCCTT C TCGGTCCT 592 Retinoblastoma AGAAAAAAGGTTCAACTACGCGTGTAAATTCTACTGCAAATG 593 Ser634Term CAGAGACACAAGCAACCT C AGCCTTCCAGACCCAGAAGCCA TCA to TGA TTGAAATCTACCTCTCTTTCACTGTTTTATAAAAAAGG CCTTTTTTATAAAACAGTGAAAGAGAGGTAGATTTCAATGGCT 594 TCTGGGTCTGGAAGGCT G AGGTTGCTTGTGTCTCTGCATTTG CAGTAGAATTTACACGCGTAGTTGAACCTTTTTTCT AGCAACCT C AGCCTTCC 595 GGAAGGCT G AGGTTGCT 596 Retinoblastoma AAAAAAGGTTCAACTACGCGTGTAAATTCTACTGCAAATGCA 597 Ala635Pro GAGACACAAGCAACCTCA G CCTTCCAGACCCAGAAGCCATT GCC to CCC GAAATCTACCTCTCTTTCACTGTTTTATAAAAAAGGTT AACCTTTTTTATAAAACAGTGAAAGAGAGGTAGATTTCAATGG 598 CTTCTGGGTCTGGAAGG C TGAGGTTGCTTGTGTCTCTGCATT TGCAGTAGAATTTACACGCGTAGTTGAACCTTTTTT CAACCTCA G CCTTCCAG 599 CTGGAAGG C TGAGGTTG 600 Retinoblastoma ACTACGCGTGTAAATTCTACTGCAAATGCAGAGACACAAGCA 601 Gln639Term ACCTCAGCCTTCCAGACC C AGAAGCCATTGAAATCTACCTCT CAG to TAG CTTTCACTGTTTTATAAAAAAGGTTAGTAGATGATTA TAATCATCTACTAACCTTTTTTATAAAACAGTGAAAGAGAGGT 602 AGATTTCAATGGCTTCT G GGTCTGGAAGGCTGAGGTTGCTTG TGTCTCTGCATTTGCAGTAGAATTTACACGCGTAGT TCCAGACC C AGAAGCCA 603 TGGCTTCT G GGTCTGGA 604 Retinoblastoma TTGTAATTCAAAATGAACAGTAAAAATGACTAATTTTTCTTATT 605 Leu657Pro CCCACAGTGTATCGGC T AGCCTATCTCCGGCTAAATACACTT CTA to CCA TGTGAACGCCTTCTGTCTGAGCACCCAGAATTAGA TCTAATTCTGGGTGCTCAGACAGAAGGCGTTCACAAAGTGTA 606 TTTAGCCGGAGATAGGCT A GCCGATACACTGTGGGAATAAG AAAAATTAGTCATTTTTACTGTTCATTTTGAATTACAA GTATCGGC T AGCCTATC 607 GATAGGCT A GCCGATAC 608 Retinoblastoma AATGAACAGTAAAAATGACTAATTTTTCTTATTCCCACAGTGTA 609 Arg661Trp TCGGCTAGCCTATCTC C GGCTAAATACACTTTGTGAACGCCT CGG to TGG TCTGTCTGAGCACCCAGAATTAGAACATATCATCT AGATGATATGTTCTAATTCTGGGTGCTCAGACAGAAGGCGTT 610 CACAAAGTGTATTTAGCC G GAGATAGGCTAGCCGATACACTG TGGGAATAAGAAAAATTAGTCATTTTTACTGTTCATT CCTATCTC C GGCTAAAT 611 ATTTAGCC G GAGATAGG 612 Retinoblastoma AACAGTAAAAATGACTAATTTTTCTTATTCCCACAGTGTATCG 613 Leu662Pro GCTAGCCTATCTCCGGC T AAATACACTTTGTGAACGCCTTCT CTA to CCA GTCTGAGCACCCAGAATTAGAACATATCATCTGGAC GTCCAGATGATATGTTCTAATTCTGGGTGCTCAGACAGAAGG 614 CGTTCACAAAGTGTATTT A GCCGGAGATAGGCTAGCCGATAC ACTGTGGGAATAAGAAAAATTAGTCATTTTTACTGTT TCTCCGGC T AAATACAC 615 GTGTATTT A GCCGGAGA 616 Retinoblastoma TATCGGCTAGCCTATCTCCGGCTAAATACACTTTGTGAACGC 617 Glu675Term CTTCTGTCTGAGCACCCA G AATTAGAACATATCATCTGGACC GAA to TAA CTTTTCCAGCACACCCTGCAGAATGAGTATGAACTCA TGAGTTCATACTCATTCTGCAGGGTGTGCTGGAAAAGGGTCC 618 AGATGATATGTTCTAATT C TGGGTGCTCAGACAGAAGGCGTT CACAAAGTGTATTTAGCCGGAGATAGGCTAGCCGATA AGCACCCA G AATTAGAA 619 TTCTAATT C TGGGTGCT 620 Retinoblastoma TTTGTGAACGCCTTCTGTCTGAGCACCCAGAATTAGAACATA 621 Gln685Pro TCATCTGGACCCTTTTCC A GCACACCCTGCAGAATGAGTATG CAG to CCG AACTCATGAGAGACAGGCATTTGGACCAAGTAAGAAA TTTCTTACTTGGTCCAAATGCCTGTCTCTCATGAGTTCATACT 622 CATTCTGCAGGGTGTGC T GGAAAAGGGTCCAGATGATATGTT CTAATTCTGGGTGCTCAGACAGAAGGCGTTCACAAA CCTTTTCC A GCACACCC 623 GGGTGTGC T GGAAAAGG 624 Retinoblastoma AAAACCATGTAATAAAATTCTGACTACTTTTACATCAATTTATT 625 Cys706Tyr TACTAGATTATGATGT G TTCCATGTATGGCATATGCAAAGTGA TGT to TAT AGAATATAGACCTTAAATTCAAAATCATTGTAAC GTTACAATGATTTTGAATTTAAGGTCTATATTCTTCACTTTGCA 626 TATGCCATACATGGAA C ACATCATAATCTAGTAAATAAATTGA TGTAAAAGTAGTCAGAATTTTATTACATGGTTTT TATGATGT G TTCCATGT 627 ACATGGAA C ACATCATA 628 Retinoblastoma TTCTGACTACTTTTACATCAATTTATTTACTAGATTATGATGTG 629 Cys712Arg TTCCATGTATGGCATA T GCAAAGTGAAGAATATAGACCTTAAA TGC to CGC TTCAAAATCATTGTAACAGCATACAAGGATCTTC GAAGATCCTTGTATGCTGTTACAATGATTTTGAATTTAAGGTC 630 TATATTCTTCACTTTGC A TATGCCATACATGGAACACATCATA ATCTAGTAAATAAATTGATGTAAAAGTAGTCAGAA ATGGCATATGCAAAGTG 631 CACTTTGC A TATGCCAT 632 Retinoblastoma GTATGGCATATGCAAAGTGAAGAATATAGACCTTAAATTCAAA 633 Tyr728Term ATCATTGTAACAGCATA C AAGGATCTTCCTCATGCTGTTCAG TAC to TAA GAGGTAGGTAATTTTCCATAGTAAGTTTTTTTGATA TATCAAAAAAACTTACTATGGAAAATTACCTACCTCCTGAACA 634 GGATGAGGAAGATCCTT G TATGCTGTTACAATGATTTTGAATT TAAGGTCTATATTCTTCACTTTGCATATGCCATAC ACAGCATA C AAGGATCT 635 AGATGCTT G TATGCTGT 636 Retinoblastoma TTTTTTTTTTTTTTTACTGTTGTTCCTCAGACATTCAAACGTGT 637 Glu748Term TTTGATCAAAGAAGAG G AGTATGATTCTATTATAGTATTCTATA GAG to TAG ACTCGGTCTTCATGCAGAGACTGAAAACAAATA TATTTGTTTTCAGTCTCTGCATGAAGACCGAGTTATAGAATAC 638 TATAATAGAATCATACT C CTCTTCTTTGATCAAAACACGTTTGA ATGTCTGAGGAAGAACAGTAAAAAAAAAAAAAAA AAGAAGAG G AGTATGAT 639 ATCATACT C CTCTTCTT 640 Retinoblastoma GTTTTGATCAAAGAAGAGGAGTATGATTCTATTATAGTATTCT 641 Gln762Term ATAACTCGGTCTTCATG C AGAGACTGAAAACAAATATTTTGCA CAG to TAG GTATGCTTCCACCAGGGTAGGTGAAAAGTATCCTT AAGGATACTTTTGACCTACCCTGGTGGAAGCATACTGCAAAA 642 TATTTGTTTTCAGTCTCT G CATGAAGACCGAGTTATAGAATAC TATAATAGAATCATACTCCTCTTCTTTGATCAAAAC TCTTCATG C AGAGACTG 643 CAGTCTCT G CATGAAGA 644 Retinoblastoma TAATCTACTTTTTTGTTTTTGCTCTAGCCCCCTACCTTGTCAC 645 Arg787Term CAATACCTCACATTCCT C GAAGCCCTTACAAGTTTCCTAGTTC CGA-TGA ACCCTTACGGATTCCTGGAGGGAACATCTATATTT AAATATAGATGTTCCCTCCAGGAATCCGTAAGGGTGAACTAG 646 GAAACTTGTAAGGGGCTTC G AGGAATGTGAGGTATTGGTGACA AGGTAGGGGGCTAGAGCAAAAACAAAAAAGTAGATTA ACATTCCT C GAAGCCCT 647 AGGGCTTC G AGGAATGT 648 Retinoblastoma CCTTACGGATTCCTGGAGGGAACATCTATATTTCACCCCTGA 649 Ser816Term AGAGTCCATATAAAATTT C AGAAGGTCTGCCAACACCAACAA TCA to TGA AAATGACTCCAAGATCAAGGTGTGTGTTTTCTCTTTA TAAAGAGAAAACACACACCTTGATCTTGGAGTCATTTTTGTTG 650 GTGTTGGCAGACCTTCT G AAATTTTATATGGACTCTTCAGGG GTGAAATATAGATGTTCCCTCCAGGAATCCGTAAGG TAAAATTT C AGAAGGTC 651 GACCTTCT G AAATTTTA 652

EXAMPLE 8 BRCA1 and BRCA2

Breast cancer is the second major cause of cancer death in American women, with an estimated 44,190 lives lost (290 men and 43,900 women) in the US in 1997. While ovarian cancer accounts for fewer deaths than breast cancer, it still represents 4% of all female cancers. In 1994, two breast cancer susceptibility genes were identified: BRCA1 on chromosome 17 and BRCA2 on chromosome 13. When a woman carries a mutation in either BRCA1 or BRCA2, she is at increased risk of being diagnosed with breast or ovarian cancer at some point in her life.

Ford et al., Am. J. Hum. Genet 62: 676-689 (1998) assessed the contribution of BRCA1 and BRCA2 to inherited breast cancer by linkage and mutation analysis in 237 families, each with at least 4 cases of breast cancer. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16%, suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority (76%) of families with both male and female breast cancer were due to BRCA2. The largest proportion (67%) of families due to other genes were families with 4 or 5 cases of female breast cancer only.

More than 75% of the reported mutations in the BRCA1 gene result in truncated proteins. Couch et al., Hum. Mutat. 8: 8-18, 1996. (1996) reported a total of 254 BRCA1 mutations, 132 (52%) of which were unique. A total of 221 (87%) of all mutations or 107 (81%) of the unique mutations are small deletions, insertions, nonsense point mutations, splice variants, and regulatory mutations that result in truncation or absence of the BRCA1 protein. A total of 11 disease-associated missense mutations (5 unique) and 21 variants (19 unique) as yet unclassified as missense mutations or polymorphisms had been detected. Thirty-five independent benign polymorphisms had been described. The most common mutations were 185delAG and 5382insC, which accounted for 30 (11.7%) and 26 (10.1%), respectively, of all the mutations.

Most BRCA2 mutations are predicted to result in a truncated protein product. The smallest known cancer-associated deletion removes from the C terminus only 224 of the 3,418 residues constituting BRCA2, suggesting that these terminal amino acids are critical for BRCA2 function. Studies (Spain et al., Proc. Natl. Acad. Sci. 96:13920-13925 (1999)) suggest that such truncations eliminate or interfere with 2 nuclear localization signals that reside within the final 156 residues of BRCA2, suggesting that the vast majority of BRCA2 mutants are nonfunctional because they are not translocated into the nucleus.

The attached table discloses the correcting oligonucleotide base sequences for the BRACA1 and BRACA2 oligonucleotides of the invention.

TABLE 14 BRCA1 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Breast Cancer CTGCGCTCAGGAGGCCTTCACCCTCTGCTCTGGGTAAAGTT 653 653 Met-1-Ile CATTGGAACAGAAAGAAAT G GATTTATCTGCTCTTCGCGTTG ATG to ATT AAGAAGTACAAAATGTCATTAATGCTATGCAGAAAATC GATTTTCTGCATAGCATTAATGACATTTTGTACTTCTTCAACG 654 CGAAGAGCAGATAAATC C ATTTCTTTCTGTTCCAATGAACTTT ACCCAGAGCAGAGGGTGAAGGCCTCCTGAGCGCAG AAAGAAAT G GATTTATC 655 GATAAATC C ATTTCTTT 656 Breast Cancer CTGGGTAAAGTTCATTGGAACAGAAAGAAATGGATTTATCTG 657 Val-11-Ala CTCTTCGCGTTGAAGAAGT A CAAAATGTCATTAATGCTATGCA GTA to GCA GAAAATCTTAGAGTGTCCCATCTGTCTGGAGTTGAT ATCAACTCCAGACAGATGGGACACTCTAAGATTTTCTGCATA 658 GCATTAATGACATTTTGT A CTTCTTCAACGCGAAGAGCAGATA AATCCATTTCTTTCTGTTCCAATGAACTTTACCCAG TGAAGAAG T ACAAAATG 659 CATTTTGT A CTTCTTCA 660 Breast Cancer ATGGATTTATCTCTCTTCGCGTTGAAGAAGTACAAAATGTCA 661 Ile-21-Val TTAATGCTATGCAGAAA A TCTTAGAGTGTCCCATCTGTCTGG ATC to GTC AGTTGATCAAGGAACCTGTCTCCACAAAGTGTGACC GGTCACACTTTGTGGAGACAGGTTCCTTGATCAACTCCAGAC 662 AGATGGGACACTCTAAGA T TTTCTGCATAGCATTAATGACATT TTGTACTTCTTCAACGCGAAGAGCAGATAAATCCAT TGCAGAAA A TCTTAGAG 663 CTCTAAGA T TTTCTGCA 664 Breast Cancer ATTTATCTGCTCTTCGCGTTGAAGAAGTACAAAATGTCATTAA 665 Leu-22-Ser TGCTATGCAGAAAATCT T AGAGTGTCCCATCTGTCTGGAGTT TTA to TCA GATCAAGGAACCTGTCTCCACAAAGTGTGACCACAT ATGTGGTCACACTTTGTGGAGACAGGTTCCTTGATCAACTCC 666 AGACAGATGGGACACTCT A AGATTTTCTGCATAGCATTAATG ACATTTTGTACTTCTTCAACGCGAAGAGCAGATAAAT GAAAATCT T AGAGTGTC 667 GACACTCT A AGATTTTC 668 Breast Cancer AGAAAATCTTAGAGTGTCCCATCTGTCTGGAGTTGATCAAGG 669 Cys-39-Tyr AACCTGTCTCCACAAAGT G TGACCACATATTTTGCAAATTTTG TGT to TAT CATGCTGAAACTTCTCAACCAGAAGAAAGGGCCTTC GAAGGCCCTTTCTTCTGGTTGAGAAGTTTCAGCATGCAAAAT 670 TTGCAAAATATGTGGTCA C ACTTTGTGGAGACAGGTTCCTTG ATCAACTCCAGACAGATGGGACACTCTAAGATTTTCT CACAAAGT G TGACCACA 671 TGTGGTCA C ACTTTGTG 672 Breast Cancer CACATATTTTGCAAATTTTGCATGCTGAAACTTCTCAACCAGA 673 Cys-61-Gly AGAAAGGGCCTTCACAG T GTCCTTTATGTAAGAATGATATAAC TGT to GGT CAAAAGGAGCCTACAAGAAAGTACGAGATTTAGTC GACTAAATCTCGTACTTTCTTGTAGGCTCCTTTTGGTTATATC 674 ATTCTTACATAAAGGAC A CTGTGAAGGCCCTTTCTTCTGGTT GAGAAGTTTCAGCATGCAAAATTTGCAAAATATGTG CTTCACAG T GTCCTTTA 675 TAAAGGAC A CTGTGAAG 676 Breast Cancer TTTGCAAATTTTGCATGCTGAAACTTCTCAACCAGAAGAAAGG 677 Leu-63-Stop GCCTTCACAGTGTCCTT T ATGTAAGAATGATATAACCAAAAGG TTA to TAA AGCCTACAAGAAAGTACGAGATTTAGTCAACTTGT ACAAGTTGACTAAATCTCGTACTTTCTTGTAGGCTCCTTTTGG 678 TTATATCATTCTTACAT A AAGGACACTGTGAAGGCCCTTTCTT CTGGTTGAGAAGTTTCAGCATGCAAAATTTGCAAA GTGTCCTT T ATGTAAGA 679 TCTTACAT A AAGGACAC 680 Breast Cancer TGCAAATTTTGCATGCTGAAACTTCTCAACCAGAAGAAAGGG 681 Cys-64-Arg CCTTCACAGTGTCCTTTA T GTAAGAATGATATAACCAAAAGGA TGT to CGT GCCTACAAGAAAGTACGAGATTTAGTCAACTTGTTG Breast Cancer CAACAAGTTGACTAAATCTCGTACTTTCTTGTAGGCTCCTTTT 682 Cys-64-Gly GGTTATATCATTCTTAC A TAAAGGACACTGTGAAGGCCCTTTC TGT to GGT TTCTGGTTGAGAAGTTTCAGCATGCAAAATTTGCA GTCCTTTA T GTAAGAAT 683 ATTCTTAC A TAAAGGAC 684 Breast Cancer GCAAATTTTGCATGCTGAAACTTCTCAACCAGAAGAAAGGGC 685 Cys-64-Tyr CTTCACAGTGTCCTTTAT G TAAGAATGATATAACCAAAAGGAG TGT to TAT CCTACAAGAAAGTACGAGATTTAGTCAACTTGTTGA TCAACAAGTTGACTAAATCTCGTACTTTCTTGTAGGCTCCTTT 686 TGGTTATATCATTCTTA C ATAAAGGACACTGTGAAGGCCCTTT CTTCTGGTTGAGAAGTTTCAGCATGCAAAATTTGC TCCTTTAT G TAAGAATG 687 CATTCTTA C ATAAAGGA 688 Breast Cancer CAGAAGAAAGGGCCTTCACAGTGTCCTTTATGTAAGAATGAT 689 Gln-74-Stop ATAACCAAAAGGAGCCTA C AAGAAAGTACGAGATTTAGTCAA CAA to TAA CTTGTTGAAGAGCTATTGAAAATCATTTGTGCTTTTC GAAAAGCACAAATGATTTTCAATAGCTCTTCAACAAGTTGACT 690 AAATCTCGTACTTTCTT G TAGGCTCCTTTTGGTTATATCATTCT TACATAAAGGACACTGTGAAGGCCCTTTCTTCTG GGAGCCTA C AAGAAAGT 691 ACTTTCTT G TAGGCTCC 692 Breast Cancer AGCTATTGAAAATCATTTGTGCTTTTCAGCTTGACACAGGTTT 693 Tyr-105-Cys GGAGTATGCAAACAGCT A TAATTTTGCAAAAAAGGAAAATAAC TAT to TGT TCTCCTGAACATCTAAAAGATGAAGTTTCTATCAT ATGATAGAAACTTCATCTTTTAGATGTTCAGGAGAGTTATTTT 694 CCTTTTTTGCAAAATTA T AGCTGTTTGCATACTCCAAACCTGT GTCAAGCTGAAAAGCACAAATGATTTTCAATAGCT AAACAGCT A TAATTTTG 695 CAAAATTA T AGCTGTTT 696 Breast Cancer CTACAGAGTGAACCCGAAAATCCTTCCTTGCAGGAAACCAGT 697 Asn-158-Tyr CTCAGTGTCCAACTCTCT A ACCTTGGAACTGTGAGAACTCTG AAC to TAC AGGACAAAGCAGCGGATACAACCTCAAAAGACGTCTG CAGACGTCTTTTGAGGTTGTATCCGCTGCTTTGTCCTCAGAG 698 TTCTCACAGTTCCAAGGT T AGAGAGTTGGACACTGAGACTGG TTTCCTGCAAGGAAGGATTTTCGGGTTCACTCTGTAG AACTCTCT A ACCTTGGA 699 TCCAAGGT T AGAGAGTT 700 Breast Cancer GAAACCAGTCTCAGTGTCCAACTCTCTAACCTTGGAACTGTG 701 Gln-169-Stop AGAACTCTGAGGACAAAG C AGCGGATACAACCTCAAAAGAC CAG to TAG GTCTGTCTACATTGAATTGGGATCTGATTCTTCTGAAG CTTCAGAAGAATCAGATCCCAATTCAATGTAGACAGACGTCTT 702 TTGAGGTTGTATCCGCT G CTTTGTCCTCAGAGTTCTCACAGT TCCAAGGTTAGAGAGTTGGACACTGAGACTGGTTTC GGACAAAG C AGCGGATA 703 TATCCGCT G CTTTGTCC 704 Breast Cancer CTCCCAGCACAGAAAAAAAGGTAGATCTGAATGCTGATCCCC 705 Trp-353-Stop TGTGTGAGAGAAAAGAAT G GAATAAGCAGAAACTGCCATGCT TGG to TAG CAGAGAATCCTAGAGATACTGAAGATGTTCCTTGGAT ATCCAAGGAACATCTTCAGTATCTCTAGGATTCTCTGAGCAT 706 GGCAGTTTCTGCTTATTC C ATTCTTTTCTCTCACACAGGGGAT CAGCATTCAGATCTACCTTTTTTTCTGTGCTGGGAG AAAAGAAT G GAATAAGC 707 GCTTATTC C ATTCTTTT 708 Breast Cancer ATGCTCAGAGAATCCTAGAGATACTGAAGATGTTCCTTGGAT 709 Ile-379-Met AACACTAAATAGCAGCAT T CAGAAAGTTAATGAGTGGTTTTCC ATT to ATG AGAAGTGATGAACTGTTAGGTTCTGATGACTCACAT ATGTGAGTCATCAGAACCTAACAGTTCATCACTTCTGGAAAAC 710 CACTCATTAACTTTCTG A ATGCTGCTATTTAGTGTTATCCAAG GAACATCTTCAGTATCTCTAGGATTCTCTGAGCAT AGCAGCAT T CAGAAAGT 711 ACTTTCTG A ATGCTGCT 712 Breast Cancer GGGAGTCTGAATCAAATGCCAAAGTAGCTGATGTATTGGACG 713 Glu-421-Gly TTCTAAATGAGGTAGATG A ATATTCTGGTTCTTCAGAGAAAAT GAA to GGA AGACTTACTGGCCAGTGATCCTCATGAGGCTTTAAT ATTAAAGCCTCATGAGGATCACTGGCCAGTAAGTCTATTTTCT 714 CTGAAGAACCAGAATAT T CATCTACCTCATTTAGAACGTCCAA TACATCAGCTACTTTGGCATTTGATTCAGACTCCC GGTAGATG A ATATTCTG 715 CAGAATAT T CATCTACC 716 Breast Cancer ATATGTAAAAGTGAAAGAGTTCACTCCAAATCAGTAGAGAGTA 717 Phe-461-Leu ATATTGAAGACAAAATA T TTGGGAAAACCTATCGGAAGAAGG TTT to CTT CAAGCCTCCCCAACTTAAGCCATGTAACTGAAAATC GATTTTCAGTTACATGGCTTAAGTTGGGGAGGCTTGCCTTCT 718 TCCGATAGGTTTTCCCAA A TATTTTGTCTTCAATATTACTCTCT ACTGATTTGGAGTGAACTCTTTCACTTTTACATAT ACAAAATA T TTGGGAAA 719 TTTCCCAA A TATTTTGT 720 Breast Cancer GAAAGAGTTCACTCCAAATCAGTAGAGAGTAATATTGAAGAC 721 Tyr-465-Leu AAAATATTTGGGAAAACC T ATCGGAAGAAGGCAAGCCTCCCC TAT to GAT AACTTAAGCCATGTAACTGAAAATCTAATTATAGGAG CTCCTATAATTAGATTTTCAGTTACATGGCTTAAGTTGGGGAG 722 GCTTGCCTTCTTCCGAT A GGTTTTCCCAAATATTTTGTCTTCA ATATTACTCTCTACTGATTTGGAGTGAACTCTTTC GGAAAACC T ATCGGAAG 723 CTTCCGAT A GGTTTTCC 724 Breast Cancer ACCTATCGGAAGAAGGCAAGCCTCCCCAACTTAAGCCATGTA 725 Gly-484-Stop ACTGAAAATCTAATTATA G GAGCATTTGTTACTGAGCCACAGA GGA to TGA TAATACAAGAGCGTCCCCTCACAAATAAATTAAAGC GCTTTAATTTATTTGTGAGGGGACGCTCTTGTATTATCTGTGG 726 CTCAGTAACAAATGCTC C TATAATTAGATTTTCAGTTACATGG CTTAAGTTGGGGAGGCTTGCCTTCTTCCGATAGGT TAATTATA G GAGCATTT 727 AAATGCTC C TATAATTA 728 Breast Cancer TTACTGAGCCACAGATAATACAAGAGCGTCCCCTCACAAATA 729 Arg-507-Ile AATTAAAGCGTAAAAGGA G ACCTACATCAGGCCTTCATCCTG AGA to ATA AGGATTTTATCAAGAAAGCAGATTTGGCAGTTCAAAA TTTTGAACTGCCAAATCTGCTTTCTTGATAAAATCCTCAGGAT 730 GAAGGCCTGATGTAGGT C TCCTTTTACGCTTTAATTTATTTGT GAGGGGACGCTCTTGTATTATCTGTGGCTCAGTAA TAAAAGGA G ACCTACAT 731 ATGTAGGT C TCCTTTTA 732 Breast Cancer CACAGATAATACAAGAGCGTCCCCTCACAAATAAATTAAAGC 733 Ser-510-Stop GTAAAAGGAGACCTACAT C AGGCCTTCATCCTGAGGATTTTA TCA to TGA TCAAGAAAGCAGATTTGGCAGTTCAAAAGACTCCTGA Q TCAGGAGTCTTTTGAACTGCCAAATCTGCTTTCTTGATAAAAT 734 CCTCAGGATGAAGGCCT G ATGTAGGTCTCCTTTTACGCTTTA ATTTATTTGTGAGGGGACGCTCTTGTATTATCTGTG ACCTACAT C AGGCCTTC 735 GAAGGCCT G ATGTAGGT 736 Breast Cancer AGGAGACCTACATCAGGCCTTCATCCTGAGGATTTTATCAAG 737 Gln-526-Stop AAAGCAGATTTGGCAGTT C AAAAGACTCCTGAAATGATAAATC CAA to TAA AGGGAACTAACCAAACGGAGCAGAATGGTCAAGTGA TCACTTGACCATTCTGCTCCGTTTGGTTAGTTCCCTGATTTAT 738 CATTTCAGGAGTCTTTT G AACTGCCAAATCTGCTTTCTTGATA AAATCCTCAGGATGAAGGCCTGATGTAGGTCTCCT TGGCAGTT C AAAAGACT 739 AGTCTTTT G AACTGCCA 740 Breast Cancer AGGAGACCTACATCAGGCCTTCATCCTGAGGATTTTATCAAG 741 Gln-541-Stop AAAGCAGATTTGGCAGTT C AAAAGACTCCTGAAATGATAAATC CAG to TAG AGGGAACTAACCAAACGGAGCAGAATGGTCAAGTGA TCACTTGACCATTCTGCTCCGTTTGGTTAGTTCCCTGATTTAT 742 CATTTCAGGAGTCTTTT G AACTGCCAAATCTGCTTTCTTGATA AAATCCTCAGGATGAAGGCCTGATGTAGGTCTCCT AAACGGAG C AGAATGGT 743 ACCATTCT G CTCCGTTT 744 Breast Cancer TAAATCAGGGAACTAACCAAACGGAGCAGAATGGTCAAGTGA 745 Gly-552-Val TGAATATTACTAATAGTG G TCATGAGAATAAAACAAAAGGTGA GGT to GTT TTCTATTCAGAATGAGAAAAATCCTAACCCAATAGA TCTATTGGGTTAGGATTTTTCTCATTCTGAATAGAATCACCTTT 746 TGTTTTATTCTCATGA C CACTATTAGTAATATTCATCACTTGAC CATTCTGCTCCGTTTGGTTAGTTCCCTGATTTA TAATAGTG G TCATGAGA 747 TCTCATGA C CACTATTA 748 Breast Cancer GGTCAAGTGATGAATATTACTAATAGTGGTCATGAGAATAAAA 749 Gln-563-Stop CAAAAGGTGATTCTATT C AGAATGAGAAAAATCCTAACCCAAT CAT to TAG AGAATCACTCGAAAAAGAATCTGCTTTCAAAACGA TCGTTTTGAAAGCAGATTCTTTTTCGAGTGATTCTATTGGGTT 750 AGGATTTTTCTCATTCT G AATAGAATCACCTTTTGTTTTATTCT CATGACCACTATTAGTAATATTCATCACTTGACC ATTCTATT C AGAATGAG 751 CTCATTCT G AATAGAAT 752 Ovarian Cancer ATAAGCAGCAGTATAAGCAATATGGAACTCGAATTAAATATCC 753 Lys-607-Stop ACAATTCAAAAGCACCT A AAAAGAATAGGCTGAGGAGGAAGT AAA to TAA CTTCTACCAGGCATATTCATGCGCTTGAACTAGTAG CTACTAGTTCAAGCGCATGAATATGCCTGGTAGAAGACTTCC 754 TCCTCAGCCTATTCTTTT T AGGTGCTTTTGAATTGTGGATATT TAATTCGAGTTCCATATTGCTTATACTGCTGCTTAT AAGCACCT A AAAAGAAT 755 ATTCTTTT T AGGTGCTT 756 Breast Cancer ATATTCATGCGCTTGAACTAGTAGTCAGTAGAAATCTAAGCCC 757 Leu-639-Stop ACCTAATTGTACTGAAT T GCAAATTGATAGTTGTTCTAGCAGT TTG to TAG GAAGAGATAAAGAAAAAAAAGTACAACCAAATGCC GGCATTTGGTTGTACTTTTTTTTCTTTATCTCTTCACTGCTAGA 758 ACAACTATCAATTTGC A ATTCAGTACAATTAGGTGGGCTTAGA TTTCTACTGACTACTAGTTCAAGCGCATGAATAT TACTGAAT T GCAAATTG 759 CAATTTGC A ATTCAGTA 760 Breast Cancer GAACCTGCAACTGGAGCCAAGAAGAGTAACAAGCCAAATGAA 761 Asp-693-Asn CAGACAAGTAAAAGACAT G ACAGCGATACTTTCCCAGAGCTG GAC to AAC AAGTTAACAAATGCACCTGGTTCTTTTACTAAGTGTT AACACTTAGTAAAAGAACCAGGTGCATTTGTTAACTTCAGCTC 762 TGGGAAAGTATCGCTGT C ATGTCTTTTACTTGTCTGTTCATTT GGCTTGTTACTCTTCTTGGCTCCAGTTGCAGGTTC AAAGACAT G ACAGCGAT 763 ATCGCTGT C ATGTCTTT 764 Ovarian Cancer CTGAAGTTAACAAATGCACCTGGTTCTTTTACTAAGTGTTCAA 765 Glu-720-Stop ATACCAGTGAACTTAAA G AATTTGTCAATCCTAGCCTTCCAAG GAA to TAA AGAAGAAAAAGAAGAGAAACTAGAAACAGTTAAAG CTTTAACTGTTTCTAGTTTCTCTTCTTTTTCTTCTCTTGGAAGG 766 CTAGGATTGACAAATT C TTTAAGTTCACTGGTATTTGAACACT TAGTAAAAGAACCAGGTGCATTTGTTAACTTCAG AACTTAAA G AATTTGTC 767 GACAAATT C TTTAAGTT 768 Breast Cancer CTAGAAACAGTTAAAGTGTCTAATAATGCTGAAGACCCCAAA 769 Glu-755-Stop GATCTCATGTTAAGTGGA G AAAGGGTTTTGCAAACTGAAAGA GAA to TAA TCTGTAGAGAGTAGCAGTATTTCATTGGTACCTGGTA TACCAGGTACCAATGAAATACTGCTACTCTCTACAGATCTTTC 770 AGTTTGCAAAACCCTTT C TCCACTTAACATGAGATCTTTGGGG TCTTCAGCATTATTAGACACTTTAACTGTTTCTAG TAAGTGGA G AAAGGGTT 771 AACCCTTT C TCCACTTA 772 Breast Cancer TCATGTTAAGTGGAGAAAGGGTTTTGCAAACTGAAAGATCTG 773 Ser-770-Stop TAGAGAGTAGCAGTATTT C ATTGGTACCTGGTACTGATTATG TCA to TAA GCACTCAGGAAAGTATCTCGTTACTGGAAGTTAGCAC GTGCTAACTTCCAGTAACGAGATACTTTCCTGAGTGCCATAA 774 TCAGTACCAGGTACCAAT G AAATACTGCTACTCTCTACAGAT CTTTCAGTTTGCAAAACCCTTTCTCCACTTAACATGA CAGTATTT C ATTGGTAC 775 GTACCAAT G AAATACTG 776 Breast Cancer TAAGTGGAGAAAGGGTTTTGCAAACTGAAAGATCTGTAGAGA 777 Val-772-Ala GTAGCAGTATTTCATTGG T ACCTGGTACTGATTATGGCACTC GTA to GCA AGGAAAGTATCTCGTTACTGGAAGTTAGCACTCTAGG CCTAGAGTGCTAACTTCCAGTAACGAGATACTTTCCTGAGTG 778 CCATAATCAGTACCAGGT A CCAATGAAATACTGCTACTCTCTA CAGATCTTTCAGTTTGCAAAACCCTTTCTCCACTTA TTCATTGG T ACCTGGTA 779 TACCAGGT A CCAATGAA 780 Breast Cancer ACTGAAAGATCTGTAGAGAGTAGCAGTATTTCATTGGTACCT 781 Gln-780-Stop GGTACTGATTATGGCACT C AGGAAAGTATCTCGTTACTGGAA CAG to TAG GTTAGCACTCTAGGGAAGGCAAAAACAGAACCAAATA TATTTGGTTCTGTTTTTGCCTTCCCTAGAGTGCTAACTTCCAG 782 TAACGAGATACTTTCCT G AGTGCCATAATCAGTACCAGGTAC CAATGAAATACTGCTACTCTCTACAGATCTTTCAGT ATGGCACT C AGGAAAGT 783 ACTTTCCT G AGTGCCAT 784 Breast Cancer TATGGCACTCAGGAAAGTATCTCGTTACTGGAAGTTAGCACT 785 Glu-797-Stop CTAGGGAAGGCAAAAACA G AACCAAATAAATGTGTGAGTCAG GAA to TAA TGTGCAGCATTTGAAAACCCCAAGGGACTAATTCATG CATGAATTAGTCCCTTGGGGTTTTCAAATGCTGCACACTGAC 786 TCACACATTTATTTGGTT C TGTTTTTGCCTTCCCTAGAGTGCT AACTTCCAGTAACGAGATACTTTCCTGAGTGCCATA CAAAAACA G AACCAAAT 787 ATTTGGTT C TGTTTTTG 788 Breast Cancer AAATGTGTGAGTCAGTGTGCAGCATTTGAAAACCCCAAGGGA 789 Lys-820-Glu CTAATTCATGGTTGTTCC A AAGATAATAGAAATGACACAGAAG AAA to GAA GCTTTAAGTATCCATTGGGACATGAAGTTAACCACA TGTGGTTAACTTCATGTCCCAATGGATACTTAAAGCCTTCTGT 790 GTCATTTCTATTATCTT T GGAACAACCATGAATTAGTCCCTTG GGGTTTTCAAATGCTGCACACTGACTCACACATTT GTTGTTCC A AAGATAAT 791 ATTATCTT T GGAACAAC 792 Breast Cancer CAGCATTTGAAAACCCCAAGGGACTAATTCATGGTTGTTCCA 793 Thr-826-Lys AAGATAATAGAAATGACA C AGAAGGCTTTAAGTATCCATTGG ACA to AAA GACATGAAGTTAACCACAGTCGGGAAACAAGCATAGA TCTATGCTTGTTTCCCGACTGTGGTTAACTTCATGTCCCAATG 794 GATACTTAAAGCCTTCT G TGTCATTTCTATTATCTTTGGAACA ACCATGAATTAGTCCCTTGGGGTTTTCAAATGCTG AAATGACA C AGAAGGCT 795 AGCCTTCT G GTCATTT 796 Breast Cancer GATAATAGAAATGACACAGAAGGCTTTAAGTATCCATTGGGA 797 Arg-841-Trp CATGAAGTTAACCACAGT T GGGAAACAAGCATAGAAATGGAA CGG to TGG GAAAGTGAACTTGATGCTCAGTATTTGCAGAATACAT ATGTATTCTGCAAATACTGAGCATCAAGTTCACTTTCTTCCAT 798 TTCTATGCTTGTTTCCC G ACTGTGGTTAACTTCATGTCCCAAT GGATACTTAAAGCCTTCTGTGTCATTTCTATTATC ACCACAGT C GGGAAACA 799 TGTTTCCC G ACTGTGGT 800 Breast Cancer AACTTGATGCTCAGTATTTGCAGAATACATTCAAGGTTTCAAA 801 Pro-871-Leu GCGCCAGTCATTTGCTC C GTTTTCAAATCCAGGAAATGCAGA CCG to CTG AGAGGAATGTGCAACATTCTCTGCCCACTCTGGGTC GACCCAGAGTGGGCAGAGAATGTTGCACATTCCTCTTCTGCA 802 TTTCCTGGATTTGAAAAC G GAGCAAATGACTGGCGCTTTGAA ACCTTGAATGTATTCTGCAAATACTGAGCATCAAGTT ATTTGCTC C GTTTTCAA 803 TTGAAAAC G GAGCAAAT 804 Breast Cancer TTTCAAATCCAGGAAATGCAGAAGAGGAATGTGCAACATTCT Leu-892-Ser CTGCCCACTCTGGGTCCT T AAAGAAACAAAGTCCAAAAGTCA TTA to TCA CTTTTGAATGTGAACAAAAGGAAGAAAATCAAGGAAA TTTCCTTGATTTTCTTCCTTTTGTTCACATTCAAAAGTGACTTT 806 TGGACTTTGTTTCTTT A AGGACCCAGAGTGGGCAGAGAATGT TGCACATTCCTCTTCTGCATTTCCTGGATTTGAAA TGGGTCCT T AAAGAAAC 807 GTTTCTTT A AGGACCCA 808 Breast Cancer CACTCTGGGTCCTTAAAGAAACAAAGTCCAAAAGTCACTTTTG 809 Glu-908-Stop AATGTGAACAAAAGGAA G AAAATCAAGGAAAGAATGAGTCTA GAA to TAA ATATCAAGCCTGTACAGACAGTTAATATCACTGCAG CTGCAGTGATATTAACTGTCTGTACAGGCTTGATATTAGACTC 810 ATTCTTTCCTTGATTTT C TTCCTTTTGTTCACATTCAAAAGTGA CTTTTGGACTTTGTTTCTTTAAGGACCCAGAGTG AAAAGGAA G AAAATCAA 811 TTGATTTT C TTCCTTTT 812 Breast Cancer ATAATGCCAAATGTAGTATCAAAGGAGGCTCTAGGTTTTGTCT 813 Gly-960-Asp ATCATCTCAGTTCAGAG G CAACGAAACTGGACTCATTACTCC GGC to GAC AAATAAACATGGACTTTTACAAAACCCATATCGTAT ATACGATATGGGTTTTGTAAAAGTCCATGTTTATTTGGAGTAA 814 TGAGTCCAGTTTCGTTG C CTCTGAACTGAGATGATAGACAAA ACCTAGAGCCTCCTTTGATACTACATTTGGCATTAT GTTCAGAG G CAACGAAA 815 TTTCGTTG C CTCTGAAC 816 Breast Cancer ATTTGTTAAAACTAAATGTAAGAAAAATCTGCTAGAGGAAAAC 817 Met-1008-Ile TTTGAGGAACATTCAAT G TCACCTGAAAGAGAAATGGGAAAT ATG to ATA GAGAACATTCCAAGTACAGTGAGCACAATTAGCCGT ACGGCTAATTGTGCTCACTGTACTTGGAATGTTCTCATTTCCC 818 ATTTCTCTTTCAGGTGA C ATTGAATGTTCCTCAAAGTTTTCCT CTAGCAGATTTTTCTTACATTTAGTTTTAACAAAT CATTCAAT G TCACCTGA 819 TCAGGTGA C ATTGAATG 820 Breast Cancer ACTTTGAGGAACATTCAATGTCACCTGAAAGAGAAATGGGAA 821 Thr-1025-Ile ATGAGAACATTCCAAGTA C AGTGAGCACAATTAGCCGTAATA ACA to ATA ACATTAGAGAAAATGTTTTTAAAGAAGCCAGCTCAAG CTTGAGCTGGCTTCTTTAAAAACATTTTCTCTAATGTTATTACG 822 GCTAATTGTGCTCACT G TACTTGGAATGTTCTCATTTCCCATT TCTCTTTCAGGTGACATTGAATGTTCCTCAAAGT TCCAAGTA C AGTGAGCA 823 TGCTCACT G TACTTGGA 824 Breast Cancer ACATTCCAAGTACAGTGAGCACAATTAGCCGTAATAACATTAG 825 Glu-1038-Gly AGAAAATGTTTTTAAAG A AGCCAGCTCAAGCAATATTAATGAA GAA to GGA GTAGGTTCCAGTACTAATGAAGTGGGCTCCAGTAT ATACTGGAGCCCACTTCATTAGTACTGGAACCTACTTCATTAA 826 TATTGCTTGAGCTGGCT T CTTTAAAAACATTTTCTCTAATGTTA TTACGGCTAATTGTGCTCACTGTACTTGGAATGT TTTTAAAG A AGCCAGCT 827 AGCTGGCT T CTTTAAAA 828 Breast Cancer CAAGTACAGTGAGCACAATTAGCCGTAATAACATTAGAGAAA 829 Ser-1040-Asn ATGTTTTTAAAGAAGCCA G CTCAAGCAATATTAATGAAGTAGG AGC to AAC TTCCAGTACTAATGAAGTGGGCTCCAGTATTAATGA TCATTAATACTGGAGCCCACTTCATTAGTACTGGAACCTACTT 830 CATTAATATTGCTTGAG C TGGCTTCTTTAAAAACATTTTCTCTA ATGTTATTACGGCTAATTGTGCTCACTGTACTTG AGAAGCCA G CTCAAGCA 831 TGCTTGAG C TGGCTTCT 832 Breast Cancer GCCGTAATAACATTAGAGAAAATGTTTTTAAAGAAGCCAGCTC 833 Val-1047-Ala AAGCAATATTAATGAAG T AGGTTCCAGTACTAATGAAGTGGG GTA to GCA CTCCAGTATTAATGAAATAGGTTCCAGTGATGAAAA TTTTCATCACTGGAACCTATTTCATTAATACTGGAGCCCACTT 834 CATTAGTACTGGAACCT A CTTCATTAATATTGCTTGAGCTGGC TTCTTTAAAAACATTTTCTCTAATGTTATTACGGC TAATGAAG T AGGTTCCA 835 TGGAACCT A CTTCATTA 836 Breast Cancer AAATAGGTTCCAGTGATGAAAACATTCAAGCAGAACTAGGTA 837 Leu-1080-Stop GAAACAGAGGGCCAAAAT T GAATGCTATGCTTAGATTAGGGG TTG to TAG TTTTGCAACCTGAGGTCTATAAACAAAGTCTTCCTGG CCAGGAAGACTTTGTTTATAGACCTCAGGTTGCAAAACCCCT 838 AATCTAAGCATAGCATTC A ATTTTGGCCCTCTGTTTCTACCTA GTTCTGCTTGAATGTTTTCATCACTGGAACCTATTT GCCAAAAT T GAATGCTA 839 TAGCATTC A ATTTTGGC 840 Breast Cancer AAAACATTCAAGCAGAACTAGGTAGAAACAGAGGGCCAAAAT 841 Leu-1086-Stop TGAATGCTATGCTTAGAT T AGGGGTTTTGCAACCTGAGGTCT TTA to TGA ATAAACAAAGTCTTCCTGGAAGTAATTGTAAGCATCC GGATGCTTACAATTACTTCCAGGAAGACTTTGTTTATAGACCT 842 CAGGTTGCAAAACCCCT A ATCTAAGCATAGCATTCAATTTTG GCCCTCTGTTTCTACCTAGTTCTGCTTGAATGTTTT GCTTAGAT T AGGGGTTT 843 AAACCCCT A ATCTAAGC 844 Breast Cancer AGCAAGAATATGAAGAAGTAGTTCAGACTGTTAATACAGATTT 845 Ser-1130-Stop CTCTCCATATCTGATTT C AGATAACTTAGAACAGCCTATGGGA TCA to TGA AGTAGTCATGCATCTCAGGTTTGTTCTGAGACACC GGTGTCTCAGAACAAACCTGAGATGCATGACTACTTCCCATA 846 GGCTGTTCTAAGTTATCT G AAATCAGATATGGAGAGAAATCT GTATTAACAGTCTGAACTACTTCTTCATATTCTTGCT TCTGATTT C AGATAACT 847 AGTTATCT G AAATCAGA 848 Breast Cancer CTAGTTTTGCTGAAAATGACATTAAGGAAAGTTCTGCTGTTTT 849 Lys-1183-Arg TAGCAAAAGCGTCCAGA A AGGAGAGCTTAGCAGGAGTCCTA AAA to AGA GCCCTTTCACCCATACACATTTGGCTCAGGGTTACCG CGGTAACCCTGAGCCAAATGTGTATGGGTGAAAGGGCTAGG 850 ACTCCTGCTAAGCTCTCCT T TCTGGACGCTTTTGCTAAAAACA GCAGAACTTTCCTTAATGTCATTTTCAGCAAAACTAG CGTCCAGA A AGGAGAGC 851 GCTCTCCT T TCTGGACG 852 Breast Cancer AGCGTCCAGAAAGGAGAGCTTAGCAGGAGTCCTAGCCCTTT 853 Gln-1200-Stop CACCCATACACATTTGGCT C AGGGTTACCGAAGAGGGGCCA CAG to TAG AGAAATTAGAGTCCTCAGAAGAGAACTTATCTAGTGAGG CCTCACTAGATAAGTTCTCTTCTGAGGACTCTAATTTCTTGGC 854 CCCTCTTCGGTAACCCT G AGCCAAATGTGTATGGGTGAAAGG GCTAGGACTCCTGCTAAGCTCTCCTTTCTGGACGCT ATTTGGCT C AGGGTTAC 855 GTAACCCT G AGCCAAAT 856 Breast Cancer AAAGGAGAGCTTAGCAGGAGTCCTAGCCCTTTCACCCATACA 857 Arg-1203-Stop CATTTGGCTCAGGGTTAC C GAAGAGGGGCCAAGAAATTAGA CAG to TAG GTCCTCAGAAGAGAACTTATCTAGTGAGGATGAAGAGC GCTCTTCATCCTCACTAGATAAGTTCTCTTCTGAGGACTCTAA 858 TTTCTTGGCCCCTCTTC G GTAACCCTGAGCCAAATGTGTATG GGTGAAAGGGCTAGGACTCCTGCTAAGCTCTCCTTT AGGGTTAC C GAAGAGGG 859 CCCTCTTC G GTAACCCT 860 Breast Cancer ACCCATACATTTGGCTCAGGGTTACCGAAGAGGGGCCAA 861 Glu-1214-Stop GAAATTAGAGTCCTCAGAA G AGAACTTATCTAGTGAGGATGA GAG to TAG AGAGCTTCCCTGCTTCCAACACTTGTTATTTGGTAAAG CTTTACCAAATAACAAGTGTTGGAAGCAGGGAAGCTCTTCAT 862 CCTCACTAGATAAGTTCT C TTCTGAGGACTCTAATTTCTTGGC CCCTCTTCGGTAACCCTGAGCCAAATGTGTATGGGT CCTCAGAA G AGAACTTA 863 TAAGTTCT C TTCTGAGG 864 Breast Cancer TCAGGGTTACCGAAGAGGGGCCAAGAAATTAGAGTCCTCAG 865 Glu-1219-Asp AAGAGAACTTATCTAGTGA G GATGAAGAGCTTCCCTGCTTCC GAG to GAC AACACTTGTTATTTGGTAAAGTAAACAATATACCTTCT AGAAGGTATATTGTTTACTTTACCAAATAACAAGTGTTGGAAG 866 CAGGGAAGCTCTTCATC C TCACTAGATAAGTTCTCTTCTGAG GACTCTAATTTCTTGGCCCCTCTTCGGTAACCCTGA TCTAGTGA G GATGAAGA 867 TCTTCATC C TCACTAGA 868 Breast Cancer GGTTACCGAAGAGGGGCCAAGAAATTAGAGTCCTCAGAAGA 869 Glu-1221-Stop GAACTTATCTAGTGAGGAT G AAGAGCTTCCCTGCTTCCAACA GAA to TAA CTTGTTATTTGGTAAAGTAAACAATATACCTTCTCAGT ACTGAGAAGGTATATTGTTTACTTTACCAAATAACAAGTGTTG 870 GAAGCAGGGAAGCTCTT C ATCCTCACTAGATAAGTTCTCTTC TGAGGACTCTAATTTCTTGGCCCCTTCGGTAACC GTGAGGAT G AAGAGCTT 871 AAGCTCTT C ATCCTCAC 872 Breast Cancer TTATTTGGTAAACAATATACCTTCTCAGTCTACTAGGC 873 Glu-1250-Stop ATAGCACCGTTGCTACC G AGTGTCTGTCTAAGAACACAGAGG GAG to TAG AGAATTTATTATCATTGAAGAATAGCTTAAATGACT AGTCATTTAAGCTATTCTTCAATGATAATAAATTCTCCTCTGTG 874 TTCTTAGACAGACACT C GGTAGCAACGGTGCTATGCCTAGTA GACTGAGAAGGTATATTGTTTACTTTACCAAATAA TTGCTACC G AGTGTCTG 875 CAGACACT C GGTAGCAA 876 Breast Cancer CTAGGCATAGCACCGTTGCTACCGACTGTCTGTCTAAGAACA 877 Ser-1262-Stop CAGAGGAGAATTTATTAT C ATTGAAGAATAGCTTAAATGACTG TCA to TAA CAGTAACCAGGTAATATTGGCAAAGGCATCTCAGGA TCCTGAGATGCCTTTGCCAATATTACCTGGTTACTGCAGTCAT 878 TTAAGCTATTCTTCAAT G ATAATAAATTCTCCTCTGTGTTCTTA GACAGACACTCGGTAGCAACGGTGCTATGCCTAG TTTATTAT C ATTGAAGA 879 TCTTCAAT G ATAATAAA 880 Breast Cancer TTATCATTGAAGAATAGCTTAAATGACTGCAGTAACCAGGTAA 881 GlN-1281-Stop TATTGGCAAAGGCATCT C AGGAACATCACCTTAGTGAGGAAA CAG to TAG CAAAATGTTCTGCTAGCTTGTTTTCTTCACAGTGCA TGCACTGTGAAGAAAACAAGCTAGCAGAACATTTTGTTTCCTC 882 ACTAAGGTGATGTTCCT G AGATGCCTTTGCCAATATTACCTG GTTACTGCAGTCATTTAAGCTATTCTTCAATGATAA AGGCATCT C AGGAACAT 883 ATGTTCCT G AGATGCCT 884 Breast Cancer GCTAGCTTGTTTTCTTCACAGTGCAGTGAATTGGAAGACTTG 885 GlN-1313-Stop ACTGCAAATACAAACACC C AGGATCCTTTCTTGATTCTT CAG to TAG CCAAACAAATGAGGCATCAGTCTGAAAGCCAGGGAG CTCCCTGGCTTTCAGACTGATGCCTCATTTGTTGGAAGAAC 886 CAATCAAGAAAGGATCCT G GGTGTTTGTATTTGCAGTCAAGT CTTCCAATTCACTGCACTGTGAAGAAAACAAGCTAGC CAAACACC C AGGATCCT 887 AGGATCCT G GGTGTTTG 888 Breast Cancer TCACAGTGCAGTGAATTGGAAGACTTGACTGCAAATACAAAC 889 GlN-1318-Stop ACCCAGGATCCTTTCTTG A TTGGTTCTTCCAAACAAATGAGG ATT to GTT CATCAGTCTGAAAGCCAGGGAGTTGGTCTGAGTGACA TGTCACTCAGACCAACTCCCTGGCTTTCAGACTGATGCCTCA 890 TTTGTTTGGAAGAACCAA T CAAGAAAGGATCCTGGGTGTTTG TATTTGCAGTCAAGTCTTCCAATTCACTGCACTGTGA CTTTCTTG A TTGGTTCT 891 AGAACCAA T CAAGAAAG 892 Breast Cancer TTGGAAGACTTGACTGCAAATACAAACACCCAGGATCCTTTC 893 GlN-1323-Stop TTGATTGGTTCTTCCAAA C AAATGAGGCATCAGTCTGAAAGC CAA to TAA CAGGGAGTTGGTCTGAGTGACAAGGAATTGGTTTCAG CTGAAACCAATTCCTTGTCACTCAGACCAACTCCCTGGCTTT 894 CAGACTGATGCCTCATTT G TTTGGAAGAACCAATCAAGAAAG GATCCTGGGTGTTTGTATTTGCAGTCAAGTCTTCCAA CTTCCAAA C AAATGAGG 895 CCTCATTT G TTTGGAAG 896 Breast Cancer CAGTCTGAAAGCCAGGGAGTTGGTCTGAGTGACAAGGAATT 897 Arg-1347-Stop GGTTTCAGATGATGAAGAA A GAGGAACGGGCTTGGAAGAAA AGA to GGA ATAATCAAGAAGAGCAAAGCATGGATTCAAACTTAGGTA TACCTAAGTTTGAATCCATGCTTTGCTCTTCTTGATTATTTTCT 898 TCCAAGCCCGTTCCTC T TTCTTCATCATCTGAAACCAATTCCT TGCACTCAGACCAACTCCCTGGCTTTCAGACTG ATGAAGAA A GAGGAACG 899 CGTTCCTC T TTCTTCAT 900 Breast Cancer GAAACAAGCGTCTCTGAAGACTGCTCAGGGCTATCCTCTCAG 901 Gln-1395-Stop AGTGACATTTTAACCACT C AGGTAAAAAGCGTGTGTGTGTGT CAG to TAG GCACATGCGTGTGTGTGGTGTCCTTTGCATTCAGTAG CTACTGAATGCAAAGGACACCACACACACGCATGTGCACACA 902 CACACACGCTTTTTACCT G AGTGGTTAAAATGTCACTCTGAG AGGATAGCCCTGAGCAGTCTTCAGAGACGCTTGTTTC TAACCACT C AGGTAAAA 903 TTTTACCT G AGTGGTTA 904 Breast Cancer TGGTGCCATTTATCGTTTTTGAAGCAGAGGGATACCATGCAA 905 Gln-1408-Stop CATAACCTGATAAAGCTC C AGCAGGAAATGGCTGAACTAGAA CAG to TAG GCTGTGTTAGAACAGCATGGGAGCCAGCCTTCTAACA TGTTAGAAGGCTGGCTCCCATGCTGTTCTAACACAGCTTCTA 906 GTTCAGCCATTTCCTGCT G GAGCTTTATCAGGTTATGTTGCAT GGTATCCCTCTGCTTCAAAAACGATAAATGGCACCA TAAAGCTC C AGCAGGAA 907 TTCCTGCT G GAGCTTTA 908 Breast Cancer AGCCAGCCTTCTAACAGCTACCCTTCCATCATAAGTGACTCT 909 Arg-1443-Gly TCTGCCCTTGAGGACCTG C GAAATCCAGAACAAAGCACATCA CGA to GGA GAAAAAGGTGTGTATTGTTGGCCAAACACTGATATCT Arg-1443-Stop CGA to TGA AGATATCAGTGTTTGGCCAACAATACACACCTTTTTCTGATGT 910 GCTTTGTTCTGGATTTC G CAGGTCCTCAAGGGCAGAAGAGTC ACTTATGATGGAAGGGTAGCTGTTAGAAGGCTGGCT AGGACCTG C GAAATCCA 911 TGGATTTC G CAGGTCCT 912 Breast Cancer CAGAATAGAAACTACCCATCTCAAGAGGAGCTCATTAAGGTT 913 Ser-1512-Ile GTTGATGTGGAGGAGCAA C AGCTGGAAGAGTCTGGGCCACA AGT to ATT CGATTTGACGGAAACATCTTACTTGCCAAGGCAAGATC GATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTG 914 GCCCAGACTCTTCCAGCT G TTGCTCCTCCACATCAACAACCT TAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTG AGGAGCAA C AGCTGGAA 915 TTCCAGCT G TTGCTCCT 916 Breast Cancer ATCTTTCTAGGTCATCCCCTTCTAAATGCCCATCATTAGATGA 917 Gln-1538-Stop TAGGTGGTACATGCACA G TTGCTCTGGGAGTCTTCAGAATAG CAG to TAG AAACTACCCATCTCAAGAGGAGCTCATTAAGGTTGT ACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCT 918 GAAGACTCCCAGAGCAA C TGTGCATGTACCACCTATCATCAT ATGATGGGCATTTAGAAGGGGATGACCTAGAAAGAT CATGCACA G TTGCTCTG 919 CAGAGCAA C TGTGCATG 920 Breast Cancer CAGAATAGAAACTACCCATCTCAAGAGGAGCTCATTAAGGTT 921 Glu-1541-Stop GTTGATGTGGAGGAGCAA C AGCTGGAAGAGTCTGGGCCACA GAG to TAG CGATTTGACGGAAACATCTTACTTGCCAAGGCAAGATC GATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTG 922 GCCCAGACTCTTCCAGCT G TTGCTCCTCCACATCAACAACCT TAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTG AGGAGCAA C AGCTGGAA 923 TTCCAGCT G TTGCTCCT 924 Breast Cancer AACTACCCATCTCAAGAGGAGCTCATTAAGGTTGTTGATGTG 925 Thr-1561-Ile GAGGAGCAACAGCTGGAA G AGTCTGGGCCACACGATTTGAC ACC to ATC GGAAACATCTTACTTGCCAAGGCAAGATCTAGGTAATA TATTACCTAGATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAA 926 ATCGTGTGGCCCAGACT C TTCCAGCTGTTGCTCCTCCACATC AACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTT AGCTGGAA G AGTCTGGG 927 CCCAGACT C TTCCAGCT 928 Breast Cancer TTTGTAATTCAACATTCATCGTTGTGTAAATTAAACTTCTCCCA 929 Tyr-1563-Stop TTCCTTTCAGAGGGGAA C CCCTTACCTGGAATCTGGAATCAGC TAC to TAG CTCTTCTCTGATGACCCTGAATCTGATCCTTCTGA TCAGAAGGATCAGATTCAGGGTCATCAGAGAAGAGGCTGATT 930 CCAGATTCCAGGTAAGGG G TTCCCTCTGAAAGGAATGGGAG AAGTTTAATTTACACAACGATGAATGTTGAATTACAAA AGAGGGAA C CCCTTACC 931 GGTAAGGG G TTCCCTCT 932 Breast Cancer CAACATTCATCGTTGTGTAAATTAAACTTCTCCCATTCCTTTC 933 Leu-1564-Pro AGAGGGAACCCCTTACC T GGAATCTGGAATCAGCCTCTTCTC CTG to CCG TGATGACCCTGAATCTGATCCTTCTGAAGACAGAGC GCTCTGTCTTCAGAAGGATCAGATTCAGGGTCATCAGAGAAG 934 AGGCTGATTCCAGATTCC A GGTAAGGGGTTCCCTCTGAAAG GAATGGGAGAAGTTTAATTTACACAACGATGAATGTTG CCCTTACC T GGAATCTG 935 CAGATTCC A GGTAAGGG 936 Breast Cancer GCCCCAGAGTCAGCTCGTGTTGGCAACATACCATCTTCAACC 937 Gln-1604-Stop TCTGCATTGAAAGTTCCC C AATTGAAAGTTGCAGAATCTGCC CAA to TAA CAGAGTCCAGCTGCTGCTCATACTACTGATACTGCTG CAGCAGTATCAGTAGTATGAGCAGCAGCTGGACTCTGGGCA 938 GATTCTGCAACTTTCAATT G GGGAACTTTCAATGCAGAGGTT GAAGATGGTATGTTGCCAACACGAGCTGACTCTGGGGC AAGTTCCC C AATTGAAA 939 TTTCAATT G GGGAACTT 940 Breast Cancer GAGTCAGCTCGTGTTGGCAACATACCATCTTCAACCTCTGCA 941 Lys-1606-Glu TTGAAAGTTCCCCAATTG A AAGTTGCAGAATCTGCCCAGAGT AAA to GAA CCAGCTGCTGCTCATACTACTGATACTGCTGGGTATA TATACCCAGCAGTATCAGTAGTATGAGCAGCAGCTGGACTCT 942 GGGCAGATTCTGCAACTT T CAATTGGGGAACTTTCAATGCAG AGGTTGAAGATGGTATGTTGCCAACACGAGCTGACTC CCCAATTG A AAGTTGCA 943 TGCAACTT T CAATTGGG 944 Breast Cancer CAGAATCTGCCCAGAGTCCAGCTGCTGCTCATACTACTGATA 945 Met-1628-Thr CTGCTGGGTATAATGCAA T GGAAGAAAGTGTGAGCAGGGAG ATG to ACG AAGCCAGAATTGACAGCTTCAACAGAAAGGGTCAACAA TTGTTGACCCTTTCTGTTGAAGCTGTCAATTCTGGCTTCTCCC 946 TGCTCACACTTTCTTCC A TTGCATTATACCCAGCAGTATCAGT AGTATGAGCAGCAGCTGGACTCTGGGCAGATTCTG TAATGCAA T GGAAGAAA 947 TTTCTTCC A TtGCATTA 948 Breast Cancer GCAGAATCTGCCCAGAGTCCAGCTGCTGCTCATACTACTGAT 949 Met-1628-Val ACTGCTGGGTATAATGCA A TGGAAGAAAGTGTGAGCAGGGA ATG to GTG GAAGCCAGAATTGACAGCTTCAACAGAAAGGGTCAACA TGTTGACCCTTTCTGTTGAAGCTGTCAATTCTGGCTTCTCCCT 950 GCTCACACTTTCTTCCA T TGCATTATACCCAGCAGTATCAGTA GTATGAGCAGCAGCTGGACTCTGGGCAGATTCTGC ATAATGCA A TGGAAGAA 951 TTCTTCCA T TGCATTAT 952 Breast Cancer CTCATACTACTGATACTGCTGGGTATAATGCAATGGAAGAAA 953 Pro-1637-Leu GTGTGAGCAGGGAGAAGC C AGAATTGACAGCTTCAACAGAA CCA to CTA AGGGTCAACAAAAGAATGTCCATGGTGGTGTCTGGCCT AGGCCAGACACCACCATGGACATTCTTTTGTTGACCCTTTCT 954 GTTGAAGCTGTCAATTCT G GCTTCTCCCTGCTCACACTTTCTT CCATTGCATTATACCCAGCAGTATCAGTAGTATGAG GGAGAAGC C AGAATTGA 955 TCAATTCT G GCTTCTCC 956 Breast Cancer GAGCAGGGAGAAGCCAGAAtTGACAGCTTCAACAGAAAGGG 957 Met-1652-Ile TCAACAAAAGAATGTCCAT G GTGGTGTCTGGCCTGACCCCAG ATG to ATA AAGAATTTGTGAGTGTATCCATATGTATCTCCCTAATG CATTAGGGAGATACATATGGATACACTCACAAATTCTTCTGG 958 GGTCAGGCCAGACACCAC C ATGGACATTCTTTTGTTGACCCT TTCTGTTGAAGCTGTCAATTCTGGCTTCTCCCTGCTC ATGTCCAT G GTGGTGTC 959 GACACCAC C ATGGACAT 960 Breast Cancer CACTTCCTGATTTTGTTTTCAACTTCTAATCCTTTGAGTGTTTT 961 Glu-1694-Stop TCATTCTGCAGATGCT G AGTTTGTGTGTGAACGGACACTAA GAG to TAG ATATTTTCTAGGAATTGCGGGAGGAAAATGGGTAG CTACCCATTTTCCTCCCGCAATTCCTAGAAAATATTTCAGTGT 962 CCGTTCACACACAAACT C AGCATCTGCAGAATGAAAAACACT CAAAGGATTAGAAGTTGAAAACAAAATCAGGAAGTG CAGATGCT G AGTTTGTG 963 CACAAACT C AGCATCTG 964 Breast Cancer GTGTTTTTTCATTCTGCAGATGCTGAGTTTGTGTGTGAACGGA 965 Gly-1706-Glu CACTGAAATATTTTCTAG G AATTGCGGGAGGAAAATGGGTAG GGA to GAA TTAGCTATTTCTGTAAGTATAATACTATTTCTCCCCT AGGGGAGAAATAGTATTATACTTACAGAAATAGCTAACTACCC 966 ATTTTCCTCCCGCAATT C CTAGAAAATATTTCAGTGTCCGTTC ACACACAAACTCAGCATCIGCAGAATGAAAAACAC TTTTCTAG G AATTGCGG 967 CCGCAATT C CTAGAAAA 968 Breast Cancer TTCATTCTGCAGATGCTGAGTTTGTGTGTGAACGGACACTGA 969 Ala-1708-Glu AATATTTTCTAGGAATTG C GGGAGGAAAATGGGTAGTTAGCT GCG to GAG ATTTCTGTAAGTATAATACTATTTCTCCCCTCCTCCC GGGAGGAGGGGAGAAATAGTATTATACTTACAGAAATAGCTA 970 ACTACCCATTTTCCTCCC G CAATTCCTAGAAAATATTTCAGTG TCCGTTCACACACAAACTCAGCATCTGCAGAATGAA AGGAATTG C GGGAGGAA 971 TTCCTCCC G CAATTCCT 972 Breast Cancer CTGAGTTTGTGTGTGAACGGACACTGAAATATTTTCTAGGAAT 973 Val-1713-Ala TGCGGGAGGAAAATGGG T AGTTAGCTATTTCTGTAAGTATAA GTA to GCA TACTATTTCTCCCCTCCTCCCTTTAACACCTCAGAA TTCTGAGGTGTTAAAGGGAGGAGGGGAGAAATAGTATTATAC 974 TTACAGAAATAGCTAACT A CCCATTTTCCTCCCGCAATTCCTA GAAAATATTTCAGTGTCCGTTCACACACAAACTCAG AAAATGGG T AGTTAGCT 975 AGCTAACT A CCCATTTT 976 Breast Cancer AACGGACACTGAAATATTTTCTAGGAATTGCGGGAGGAAAAT 977 Trp-1718-Stop GGGTAGTTAGCTATTTCT G TAAGTATAATACTATTTCTCCCCT TGG to TAG CCTCCCTTTAACACCTCAGAATTGCATTTTTACACC GGTGTAAAAATGCAATTCTGAGGTGTTAAAGGGAGGAGGGG 978 AGAAATAGTATTATACTTA C AGAAATAGCTAACTACCCATTTTC CTCCCGCAATTCCTAGAAAATATTTCAGTGTCCGTT CTATTTCT G TAAGTATA 979 TATACTTA C AGAAATAG 980 Breast Cancer TTCTGCTGTATGTAACCTGTCTTTTCTATGATCTCTTTAGGGG 981 Glu-1725-Stop TGACCCAGTCTATTAAA G AAAGAAAAATGCTGAATGAGGTAA GAA to TAA GTACTTGATGTTACAAACTAACCAGAGATATTCATT AATGAATATCTCTGGTTAGTTTGTAACATCAAGTACTTACCTC 982 ATTCAGCATTTTTCTTT C TTTAATAGACTGGGTCACCCCTAAA GAGATCATAGAAAAGACAGGTTACATACAGCAGAA CTATTAAA G AAAGAAAA 983 TTTTCTTT C TTTAATAG 984 Breast Cancer TGTATGTAACCTGTCTTTTCTATGATCTCTTTAGGGGTGACCC 985 Lys-1727-Stop AGTCTATTAAAGAAAGA A AAATGCTGAATGAGGTAAGTACTTG AAA to TAA ATGTTACAAACTAACCAGAGATATTCATTCAGTCA TGACTGAATGAATATCTCTGGTTAGTTTGTAACATCAAGTACT 986 TACCTCATTCAGCATTT T TCTTTCTTTAATAGACTGGGTCACC CCTAAAGAGATCATAGAAAAGACAGGTTACATACA AAGAAAGA A AAATGCTG 987 CAGCATTT T TCTTTCTT 988 Breast Cancer TCTTTCAGCATGATTTTGAAGTCAGAGGAGATGTGGTCAATG 989 Pro-1749-Arg GAAGAAACCACCAAGGTC C AAAGCGAGCAAGAGAATCCCAG CCA to CGA GACAGAAAGGTAAAGCTCCCTCCCTCAAGTTGACAAAA TTTTGTCAACTTGAGGGAGGGAGCTTTACCTTTCTGTCCTGG 990 GATTCTCTTGCTCGCTTT G GACCTTGGTGGTTTCTTCCATTGA CCACATCTCCTCTGACTTCAAAATCATGCTGAAAGA CCAAGGTC C AAAGCGAG 991 CTCGCTTT G GACCTTGG 992 Breast Cancer CAGCATGATTTTGAAGTCAGAGGAGATGTGGTCAATGGAAGA 993 Arg-1751-Stop AACCACCAAGGTCCAAAG C GAGCAAGAGAATCCCAGGACAG CGA to TGA AAAGGTAAAGCTCCCTCCCTCAAGTTGACAAAAATCTC GAGATTTTGTCAACTTGAGGGAGGGAGCTTTACCTTTCTGT 994 CCTGGGATTCTCTTGCTC G CTTTGGACCTTGGTGGTTTCTTC CATTGACCACATCTCCTCTGACTTCAAAATCATGCTG GTCCAAAG C GAGCAAGA 995 TCTTGCTC G CTTTGGAC 996 Breast Cancer GTCAGAGGAGATGTGGTCAATGGAAGAAACCACCAAGGTCC 997 Gln-1756-Stop AAAGCGAGCAAGAGAATCC C AGGACAGAAAGGTAAAGCTCC CAG to TAG CTCCCTCAAGTTGACAAAAATCICACCCCACCACTCTGT ACAGAGTGGTGGGGTGAGATTTTTGTCAACTTGAGGGAGGG 998 AGCTTTACCTTTCTGTCCT G GGATTCTCTTGCTCGCTTTGGA CCTTGGTGGTTTCTTCCATTGACCACATCTCCTCTGAC GAGAATCC C AGGACAGA 999 TCTGTCCT G GGATTCTC 1000 Breast Cancer CTCTCTTCTTCCAGATCTTCAGGGGGCTAGAAATCTGTTGCT 1001 Met-1775-Arg ATGGGCCCTTCACCAACA T GCCCACAGGTAAGAGCCTGGGA ATG to AGG GAACCCCAGAGTTCCAGCACCAGCCTTTGTCTTACATA TATGTAAGACAAAGGCTGGTGCTGGAACTCTGGGGTTCTCCC 1002 AGGCTCTTACCTGTGGGC A TGTTGGTGAAGGGCCCATAGCA ACAGATTTCTAGCCCCCTGAAGATCTGGAAGAAGAGAG CACCAACA T GCCCACAG 1003 CTGTGGGC A TGTTGGTG 1004 Breast Cancer AGTATGCAGATTACTGCAGTGATTTTACATCTAAAATGTCCATT 1005 Trp-1782-Stop TTAGATCAACTGGAATG G ATGGTACAGCTGTGTGGTGCTTCT TGG to TGA GTGGTGAAGGAGCTTTCATCATTCACCCTTGGCACA TGTGCCAAGGGTGAATGATGAAAGCTCCTTCACCACAGAAGC 1006 ACCACACAGCTGTACCAT C CATTCCAGTTGATCTAAAATGGA CATTTAGATGTAAAATCACTGCAGTAATCTGCATACT CTGGAATG G ATGGTACA 1007 TGTACCAT C CATTCCAG 1008 Breast Cancer ATTACTGCAGTGATTTTACATCTAAATGTCCATTTTAGATCAAC 1009 Gln-1785-His TGGAATGGATGGTACA G CTGTGTGGTGCTTCTGTGGTGAAG CAG to CAT GAGCTTTCATCATTCACCCTTGGCACAGTAAGTATT AATACTTACTGTGCCAAGGGTGAATGATGAAAGCTCCTTCAC 1010 CACAGAAGCACCACACAG C TGTACCATCCATTCCAGTTGATC TAAAATGGACATTTAGATGTAAAATCACTGCAGTAAT ATGGTACA G CTGTGTGG 1011 CCACACAG C TGTACCAT 1012 Breast Cancer GTCCATTTTAGATCAACTGGAATGGATGGTACAGCTGTGTGG 1013 Glu-1794-Asp TGCTTCTGTGGTGAAGGA G CTTTCATCATTCACCCTTGGCAC GAG to GAT AGTAAGTATTGGGTGCCCTGTCAGAGAGGGAGGACAC GTGTCCTCCCTCTCTGACAGGGCACCCAATACTTACTGTGCC 1014 AAGGGTGAATGATGAAAG C TCCTTCACCACAGAAGCACCACA CAGCTGTACCATCCATTCCAGTTGATCTAAAATGGAC GTGAAGGA G CTTTCATC 1015 GATGAAAG C TCCTTCAC 1016 Breast Cancer CTCTGCTTGTGTTCTCTGTCTCCAGCAATTGGGCAGATGTGT 1017 Arg-1835-Stop GAGGCACCTGTGGTGACC C GAGAGTGGGTGTTGGACAGTGT CGA to TGA AGCACTCTACCAGTGCCAGGAGCTGGACACCTACCTGA TCAGGTAGGTGTCCAGCTCCTGGCACTGGTAGAGTGCTACA 1018 CTGTCCAACACCCACTCTC G GGTCACCACAGGTGCCTCACA CATCTGCCCAATTGCTGGAGACAGAGAACACAAGCAGAG TGGTGACC C GAGAGTGG 1019 CCACTCTC G GGTCACCA 1020 Breast Cancer TTGTGTTCTCTGTCTCCAGCAATTGGGCAGATGTGTGAGGCA 1021 Trp-1837-Arg CCTGTGGTGACCCGAGAG T GGGTGTTGGACAGTGTAGCACT TGG to CGG CTACCAGTGCCAGGAGCTGGACACCTACCTGATACCCC GGGGTATCAGGTAGGTGTCCAGCTCCTGGCACTGGTAGAGT 1022 GCTACACTGTCCAACACCC A CTCTCGGGTCACCACAGGTGC CTCACACATCTGCCCAATTGCTGGAGACAGAGAACACAA CCCGAGAG T GGGTGTTG 1023 CAACACCC A CTCTCGGG 1024 Breast Cancer TGTGTTCTCTGTCTCCAGCAATTGGGCAGATGTGTGAGGCAC 1025 Trp-1837-Stop CTGTGGTGACCCGAGAGT G GGTGTTGGACAGTGTAGCACTC TGG to TAG TACCAGTGCCAGGAGCTGGACACCTACCTGATACCCCA TGGGGTATCAGGTAGGTGTCCAGCTCCTGGCACTGGTAGAG 1026 TGCTACACTGTCCAACACC C ACTCTCGGGTCACCACAGGTG CCTCACACATCTGCCCAATTGCTGGAGACAGAGAACACA CCGAGAGT G GGTGTTGG 1027 CCAACACC C ACTCTCGG 1028

TABLE 15 BRCA2 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Breast cancer GTTAAAACTAAGGTGGGATTTTTTTTTTAAATAGATTTAGGAC 1029 PHE32LEU CAATAAGTCTTAATTGG T TTGAAGAACTTTCTTCAGAAGCTCC TTT to CTT ACCCTATAATTCTGAACCTGCAGAAGAATCTGAAC GTTCAGATTCTTCTGCAGGTTCAGAATTATAGGGTGGAGCTT 1030 CTGAAGAAAGTTCTTCAA A CCAATTAAGACTTATTGGTCCTAA ATCTATTTAAAAAAAAAATCCCACCTTAGTTTTAAC TTAATTGG T TTGAAGAA 1031 TTCTTCAA A CCAATTAA 1032 Breast cancer TAGATTTAGGACCAATAAGTCTTAATTGGTTTGAAGAACTTTC 1033 TYR42CYS TTCAGAAGCTCCACCCT A TAATTCTGAACCTGCAGAAGAATC TAT to TGT TGAACATAAAAACAACAATTACGAACCAAACCTATT AATAGGTTTGGTTCGTAATTGTTGTTTTTATGTTCAGATTCTTC 1034 TGCAGGTTCAGAATTA T AGGGTGGAGCTTCTGAAGAAGTTC TTCAAACCAATTAAGACTTATTGGTCCTAAATCTA TCCACCCT A TAATTCTG 1035 CAGAATTA T AGGGTGGA 1036 Breast cancer AAGAACTTTCTTCAGAAGCTCCACCCTATAATTCTGAACCTGC 1037 LYS53ARG AGAAGAATCTGAACATA A AAACAACAATTACGAACCAAACCTA AAA to AGA TTTAAAACTCCACAAAGGAAACCATCTTATAATCA TGATTATAAGATGGTTTCCTTTGTGGAGTTTTAAATAGGTTTG 1038 GTTCGTAATTGTTGTTT T TATGTTCAGATTCTTCTGCAGGTTC AGAATTATAGGGTGGAGCTTCTGAAGAAAGTTCTT TGAACATA A AAACAACA 1039 TGTTGTTT T TATGTTCA 1040 Breast cancer CTATTTAAAACTCCACAAAGGAAACCATCTTATAATCAGCTGG 1041 Phe81Leu CTTCAACTCCAATAATA T TCAAAGAGCAAGGGCTGACTCTGC TTC to CTC CGCTGTACCAATCTCCTGTAAAAGAATTAGATAAAT ATTTATCTAATTCTTTTACAGGAGATTGGTACAGCGGCAGAGT 1042 CAGCCCTTGCTCTTTGA A TATTATTGGAGTTGAAGCCAGCTG ATTATAAGATGGTTTCCTTTGTGGAGTTTTAAATAG CAATAATA T TCAAAGAG 1043 CTCTTTGA A TATTATTG 1044 Breast cancer GTCAGACACCAAAACATATTTCTGAAAGTCTAGGAGCTGAGG 1045 TRP194TERM TGGATCCTGATATGTCTT G GTCAAGTTCTTTAGCTACACCACC TGG to TAG CACCCTTAGTTCTACTGTGCTCATAGGTAATAATAG CTATTATTACCTATGAGCACAGTAGAACTAAGGGTGGGTGGT 1046 GTAGCTAAAGAACTTGAC C AAGACATATCAGGATCCACCTCA GCTCCTAGACTTTCAGAAATATGTTTTGGTGTCTGAC TATGTCTT G GTCAAGTT 1047 AACTTGAC C AAGACATA 1048 Breast cancer CTGAAAGTCTAGGAGCTGAGGTGGATCCTGATATGTCTTGGT 1049 PRO201ARG CAAGTTCTTTAGCTACAC C ACCCACCCTTAGTTCTACTGTGCT CCA to CGA CATAGGTAATAATAGCAAATGTGTATTTACAAGAAA TTTCTTGTAAATACACATTTGCTATTATTACCTATGAGCACAGT 1050 AGAACTAAGGGTGGGT G GTGTAGCTAAAGAACTTGACCAAGA CATATCAGGATCCACCTCAGCTCCTAGACTTTCAC AGCTACAC C ACCCACCC 1051 GGGTGGGT G GTGTAGCT 1052 Breast cancer ACAATACACATAAATTTTTATCTTACAGTCAGAAATGAAGAAG 1053 Pro222Ser CATCTGAAACTGTATTT C CTCATGATACTACTGCTGTAAGTAA CCT to TCT ATATGACATTGATTAGACTGTTGAAATTGCTAACA TGTTAGCAATTTCAACAGTCTAATCAATGTCATATTTACTTACA 1054 GCAGTAGTATCATGAG G AAATACAGTTTCAGATGCTTCTTCAT TTCTGACTGTAAGATAAAAATTTATGTGTATTGT CTGTATTT C CTCATGAT 1055 ATCATGAG G AAATACAG 1056 Breast cancer AATGGTCTCAACTAACCCTTTCAGGTCTAAATGGAGCCCAGA 1057 Leu-414-Term TGGAGAAAATACCCCTAT T GCATATTTCTTCATGTGACCAAAA TTG to TAG TATTTCAGAAAAAGACCTATTAGACACAGAGAACAA TTGTTCTCTGTGTCTAATAGGTCTTTTTCTGAAATATTTTGGTC 1058 ACATGAAGAAATATGC A ATAGGGGTATTTTCTCCATCTGGGC TCCATTTAGACCTGAAAGGGTTAGTTGAGACCATT ACCCCTAT T GCATATTT 1059 AAATATGC A ATAGGGGT 1060 Breast cancer, male AGCCTCTGAAAGTGGACTGGAAATACATACTGTTTGCTCACA 1061 Cys554Trp GAAGGAGGACTCCTTATG T CCAAATTTAATTGATAATGGAAG TGT to TGG CTGGCCAGCCACCACCACACAGAATTCTGTAGCTTTG CAAAGCTACAGAATTCTGTGTGGTGGTGGCTGGCCAGCTTC 1062 CATTATCAATTAAATTTGG A CATAAGGAGTCCTCCTTCTGTGA GCAAACAGTATGTATTTCCAGTCCACTTTCAGAGGCT TCCTTATG T CCAAATTT 1063 AAATTTGG A CATAAGGA 1064 Breast cancer AACTCTACCATGGTTTTATATGGAGACACAGGTGATAAACAA 1065 Lys944Term GCMCCCAAGTGTCAATT A AAAAAGATTTGGTTTATGTTCTTG AAA to TAA CAGAGGAGAACAAAAATAGTGTAAAGCAGCATATAA TTATATGCTGCTTTACACTATTTTTGTTCTCCTCTGCAAGAAC 1066 ATAAACCAAATCTTTTT T AATTGACACTTGGGTTGCTTGTTTAT CACCTGTGTCTCCATATAAAACCATGGTAGAGTT TGTCAATT A AAAAAGAT 1067 ATCTTTTT T AATTGACA 1068 Breast cancer, male ATGACTACTGGCACTTTTGTTGAAGAAATTACTGAAAATTACA 1069 Glu1320Term AGAGAAATACTGAAAAT G AAGATAACAAATATACTGCTGCCAG GAA to TAA TAGAAATTCTCATAACTTAGAATTTGATGGCAGTG CACTGCCATCAAATTCTAAGTTATGAGAATTTCTACTGGCAGC 1070 AGTATATTTGTTATCTT C ATTTCAGTATTTCTCTTGTAATTTTC AGTAATTTCTTCAACAAAAGTGCCAGTAGTCAT CTGAAAAT G AAGATAAC 1071 GTTATCTT C ATTTTCAG 1072 Breast cancer CATGAAACAATTAAAAAAGTGAAAGACATATTTACAGACAGTT 1073 Glu1876Term TCAGTAAAGTAATTAAG G AAAACAACGAGAATAAATCAAAAAT GAA to TAA TTGCCAAACGAAAATTATGGCAGGTTGTTACGAGG CCTCGTAACAACCTGCCATAATTTTCGTTTGGCAAATTTTTGA 1074 TTTATTCTCGTTGTTTT C CTTAATTACTTTACTGAAACTGTCTG TAAATATGTCTTTCACTTTTTTAATTGTTTCATG TAATTAAG G AAAACAAC 1075 GTTGTTTT C CTTAATTA 1076 Breast cancer TGAAAGACATATTTACAGACAGTTTCAGTAAAGTAATTAAGGA 1077 Ser1882Term AAACAACGAGAATAAAT C AAAAATTTGCCAAACGAAAATTATG TCA to TAA GCAGGTTGTTACGAGGCATTGGATGATTCAGAGGA TCCTCTGAATCATCCAATGCCTCGTAACAACCTGCCATAATTT 1078 TCGTTTGGCAAATTTTT G ATTTATTCTCGTTGTTTTCCTTAATT ACTTTACTGAAACTGTCTGTAAATATGTCTTTCA GAATAAAT C AAAAATTT 1079 AAATTTTT G ATTTATTC 1080 Breast cancer AACCAAAATATGTCTGGATTGGAGAAAGTTTCTAAAATATCAC 1081 Glu1953Term CTTGTGATGTTAGTTTG G AAACTTCAGATATATGTAAATGTAG GAA to TAA TATAGGGAAGCTTCATAAGTCAGTCTCATCTGCAA TTGCAGATGAGACTGACTTATGAAGCTTCCCTATACTACATTT 1082 ACATATATCTGAAGTTT C CAAACTAACATCACAAGGTGATATT TTAGAAACTTTCTCCAATCCAGACATATTTTGGTT TTAGTTTG G AAACTTCA 1083 TGAAGTTT C CAAACTAA 1084 Breast cancer TTAGTTTGGAAACTTCAGATATATGTAAATGTAGTATAGGGAA 1085 Ser1970Term GCTTCATAAGTCAGTCT C ATCTGCAAATACTTGTGGGATTTTT TCA to TAA AGCACAGCAAGTGGAAAATCTGTCCAGGTATCAGA TCTGATACCTGGACAGATTTTCCACTTGCTGTGCTAAAAATCC 1086 CACAAGTATTTGCAGAT G AGACTGACTTATGAAGCTTCCCTAT ACTACATTTACATATATCTGAAGTTTCCAAACTAA GTCAGTCT C ATCTGCAA 1087 TTGCAGAT G AGACTGAC 1088 Breast cancer AAGTCAGTCTCATCTGCAAATACTTGTGGGATTTTTAGCACAG 1089 Gln1987Term CAAGTGGAAAATCTGTC C AGGTATCAGATGCTTCATTACAAAA GAG to TAG CGCAAGACAAGTGTTTTCTGAAATAGAAGATAGTA TACTATCTTCTATTTCAGAAAACACTTGTCTTGCGTTTTGTAAT 1090 GAAGCATCTGATACCT G GACAGATTTTCCACTTGCTGTGCTA AAAATCCCACAAGTATTTGCAGATGAGACTGACTT AATCTGTC C AGGTATCA 1091 TGATACCT G GACAGATT 1092 Breast cancer AAAATAAGATTAATGACAATGAGATTCATCAGTTTAACAAAAA 1093 Ala2466Val CAACTCCAATCAAGCAG C AGCTGTAACTTTCACAAAGTGTGA GCA to GTA AGAAGAACCTTTAGGTATTGTATGACAATTTGTGTG CACACAAATTGTCATACAATACCTAAAGGTTCTTCTTCACACT 1094 TTGTGAAAGTTACAGCT G CTGCTTGATTGGAGTTGTTTTTGTT AAACTGATGAATCTCATTGTCATTAATCTTATTTT TCAAGCAG C AGCTGTAA 1095 TTACAGCT G CTGCTTGA 1096 Breast cancer AGGCAACGCGTCTTTCCACAGCCAGGCAGTCTGTATCTTGCA 1097 Arg2520Term AAAACATCCACTCTGCCT C GAATCTCTCTGAAAGCAGCAGTA CGA to TGA GGAGGCCAAGTCCCCTCTGCGTGTCCTCATAAACAGG CCTGTTTATGAGGACACGCAGAGGGGACTTGGCCTCCTACT 1098 GCTGCTTTCAGAGAGATTC G AGGCAGAGTGGATGTTTTTGCA AGATACAGACTGCCTGGCTGTGGAAAGACGCGTTGCCT CTCTGCCT C GAATCTCT 1099 AGAGATTC G AGGCAGAG 1100 Breast cancer ATTTCATTGAGCGCAAATATATCTGAAACTTCTAGCAATAAAA 1101 Gln2714Term CTAGTAGTGCAGATACC C AAAAAGTGGCCATTATTGAACTTA CAA to TAA CAGATGGGTGGTATGCTGTTAAGGCCCCAGTTAGATC GATCTAACTGGGCCTTAACAGCATACCACCCATCTGTAAGTT 1102 CAATAATGGCCACTTTTT G GGTATCTGCACTACTAGTTTTATT GCTAGAAGTTTCAGATATATTTGCGCTCAATGAAAT CAGATACC C AAAAAGTG 1103 CACTTTTT G GGTATCTG 1104 Breast cancer CAGAACTGGTGGGCTCTCCTGATGCCTGTACACCTCTTGAAG 1105 Leu2776Term CCCCAGAATCTCTTATGT T AAAGGTAAATTAATTTGCACTCTT TTA to TGA GGTAAAAATCAGTCATTGATTCAGTTAAATTCTAGA TCTAGAATTTAACTGAATCAATGACTGATTTTTACCAAGAGTG 1106 CAAATTAATTTACCTTT A ACATAAGAGATTCTGGGGCTTCAAG AGGTGTACAGGCATCAGGAGAGCCCACCAGTTCTG TCTTATGT T AAAGATTT 1107 AAATCTTT A ACATAAGA 1108 Breast cancer CCTTTTGTTTTCTTAGAAAACACAACAAAACCATATTTACCATC 1109 Gln2893Term ACGTGCACTAACAAGA C AGCAAGTTCGTGCTTTGCAAGATGG CAG to TAG TGCAGAGCTTTATGAAGCAGTGAAGAATGCAGCAG CTGCTGCATTCTTCACTGCTTCATAAAGCTCTGCACCATCTTG 1110 CAAAGCACGAACTTGCT G TCTTGTTAGTGCACGTGATGGTAA ATATGGTETTGTTGTGTTTTCTAAGAAAACAAAAGG TAACAAGA C AGCAAGTT 1111 AACTTGCT G TCTTGTTA 1112 Breast cancer AATCACAGGCAAATGTTGAATGATAAGAAACAAGCTCAGATC 1113 Ala2951Thr CAGTTGGAAATTAGGAAG G CCATGGAATCTGCTGAACAAAAG GCC to ACC GAACAAGGTTTATCAAGGGATGTCACAACCGTGTGGA TCCACACGGTTGTGACATCCCTTGATAAACCTTGTTCCTTTTG 1114 TTCAGCAGATTCCATGG C CTTCCTAATTTCCAACTGGATCTGA GCTTGTTTCTTATCATTCAACATTVGCCTGTGATT TTAGGAAG G CCATGGAA 1115 TTCCATGG C CTTCCTAA 1116 Breast cancer ACAATTTACTGGCAATAAAGTTTTGGATAGACCTTAATGAGGA 1117 Met3118Thr CATTATTAAGCCTCATA T GTTAATTGCTGCAAGCAACCTCCAG ATG to ACG TGGCGACCAGAATCCAAATCAGGCCTTCTTACTTT AAAGTAAGAAGGCCTGATTTGGATTCTGGTCGCCACTGGAG 1118 GTTGCTTGCAGCAATTAAC A TATGAGGCTTAATAATGTCCTCA TTAAGGTCTATCCAAAACTTTATTGCCAGTAAATTGT GCCTCATA T GTTAATTG 1119 CAATTAAC A TATGAGGC 1120 Breast cancer GACTGAAACGACGTTGTACTACATCTCTGATCAAAGAACAGG 1121 Thr3401Met AGAGTTCCCAGGCCAGTA C GGAAGAATGTGAGAAAAATAAGC ACG to ATG AGGACACAATTACAACTAAAAAATATATCTAAGCATT AATGCTTAGATATATTTTTTAGTTGTAATTGTGTCCTGCTTATT 1122 TTTCTCACATTCTTCC G TACTGGCCTGGGAACTCTCCTGTTCT TTGATCAGAGATGTAGTACAACGTCGTTTCAGTC GGCCAGTA C GGAAGAAT 1123 ATTCTTCC G TACTGGCC 1124 Breast cancer AAAGAACAGGAGAGTTCCCAGGCCAGTACGGAAGAATGTGA 1125 lle3412Val GAAAAATAAGCAGGACACA A TTACAACTAAAAAATATATCTAA ATT to GTT GCATTTGCAAAGGCGACAATAAATTATTGACGCTTAA TTAAGCGTCAATAATTTATTGTCGCCTTTTGCAAATGCTTAGAT 1126 ATATTTTTTAGTTGTAA T TGTGTCCTGCTTATTTTTCTCACATT CTTCCGTACTGGCCTGGGAACTCTCCTGTTCTTT AGGACACA A TTACAACT 1127 AGTTGTAA T TGTGTCCT 1128

EXAMPLE 9 Cystic Fibrosis—CFTR

Cystic fibrosis is a lethal disease affecting approximately one in 2,500 live Caucasian births and is the most common autosomal recessive disease in Caucasians. Patents with this disease have reduced chloride ion permeability in the secretory and absorptive cells of organs with epithelial cell linings, including the airways, pancreas, intestine, sweat glands and male genital tract. This, in turn, reduces the transport of water across the epithelia. The lungs and the GI tract are the predominant organ systems affected in this disease and the pathology is characterized by blocking of the respiratory and GI tracts with viscous mucus. The chloride impermeability in affected tissues is due to mutations in a specific chloride channel, the cystic fibrosis transmembrane conductance regulator protein (CFTR), which prevents normal passage of chloride ions through the cell membrane (Welsh et al., Neuron, 8:821-829 (1992)). Damage to the lungs due to mucus blockage, frequent bacterial infections and inflammation is the primary cause of morbidity and mortality in CF patients and, although maintenance therapy has improved the quality of patients' lives, the median age at death is still only around 30 years. There is no effective treatment for the disease, and therapeutic research is focused on gene therapy using exogenous transgenes in viral vectors and/or activating the defective or other chloride channels in the cell membrane to normalize chloride permeability (Tizzano et al., J. Pediat., 120:337-349 (1992)). However, the death of a teenage patient treated with an adenovirus vector carrying an exogenous CFTR gene in clinical trials in the late 1990's has impacted this area of research.

The oligonucleotides of the invention for correction of the CFTR gene are attached as a table.

TABLE 16 CFTR Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Cystic fibrosis AAGGATACAGACAGCGCCTGGAATTGTCAGACATATACCAAA 1129 Ala46Asp TCCCTTCTGTTGATTCTG C TGACAATCTATCTGAAAAATTGGA GCT to GAT AAGGTATGTTCATGTACATTGTTTAGTTGAAGAGAG CTCTCTTCAACTAAACAATGTACATGAACATACCTTTCCAATTT 1130 TTCAGATAGATTGTCA G CAGAATCAACAGAAGGGATTTGGTA TATGTCTGACAATTCCAGGCGCTGTCTGTATCCTT TGATTCTG C TGACAATC 1131 GATTGTCA G CAGAATCA 1132 Cystic fibrosis AGCGCCTGGAATTGTCAGACATATACCAAATCCCTTCTGTTG 1133 Ser50Tyr ATTCTGCTGACAATCTAT C TGAAAAATTGGAAAGGTATGTTCA TCT to TAT TGTACATTGTTTAGTTGAAGAGAGAAATTCATATTA TAATATGAATTTCTCTCTTCAACTAAACAATGTACATGAACATA 1134 CCTTTCCAATTTTTCA G ATAGATTGTCAGCAGAATCAACAGAA GGGATTTGGTATATGTCTGACAATTCCAGGCGCT CAATCTAT C TGAAAAAT 1135 ATTTTTCA G ATAGATTG 1136 Congenital absence of AGGACAACTAAAATATTTGCACATGCAACTTATTGGTCCCACT 1137 vas deferens TTTTATTCTTTTGCAGA G AATGGGATAGAGAGCTGGCTTCAAA Glu56Lys GAAAAATCCTAAACTCATTAATGCCCTTCGGCGAT GAA-AAA ATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTTCTTGAAGC 1138 CAGCTCTCTATCCCATT C TCTGCAAAAGAATAAAAAGTGGGA CCAATAAGTVGCATGTGCAAATATTTAGTTGTCCT TTTGCAGA G AATGGGAT 1139 ATCCCATT C TCTGCAAA 1140 Cystic fibrosis AGGACAACTAAAATATTTGCACATGCAACTTATTGGTCCCACT 1141 Trp57Gly TTTTTATTCTTTTGCAGA G AATGGGATAGAGAGCTGGCTTCAAA TGG to GGG GAAAAATCCTAAACTCATTAATGCCCTTCGGCGAT ATCGCCGAAGGGCATTAATGAGTTTTAGGATTTTTTCTTTGAAGC 1142 CAGCTCTCTATCCCATT C TCTGCAAAAGAATAAAAAGTGGGA CCAATAAGTTGCATGTGCAAATATTTTTAGTTGTCCT TTTGCAGA G AATGGGAT 1143 ATCCCATT C TCTGCAAA 1144 Cystic fibrosis AACTAAAATATTTTGCACATGCAACTTATTGGTCCCACTTTTTAT 1145 Trp57Term TCTTTTGCAGAGAATG G GATAGAGAGCTGGCTTCAAAGAAAA TGG to TGA ATCCTAAACTCATTAATGCCCTTCGGCGATGTTTT AAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTTT 1146 GAAGCCAGCTCTCTATC C CATTCTCTGCAAAAGAATAAAAAGT GGGACCAATAAGTTGCATGTGCAAATATTTTAGTT AGAGAATG G GATAGAGA 1147 TCTCTATC C CATTCTCT 1148 Congenital absence of ACTAAAATATTTGCACATGCAACTTATTGGTCCCACTTTTTATT 1149 vas deferens CTTTTGCAGAGAATGG G ATAGAGAGCTGGCTTCAAAGAAAAA Asp58Asn TCCTAAACTCATTAATGCCCTTCGGCGATGTTTTT GAT to AAT AAAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTT 1150 TGAAGCCAGCTCTCTAT C CCATTCTCTGCAAAAGAATAAAAAG TGGGACCAATAAGTTGCATGTGCAAATATTTTAGT GAGAATGG G ATAGAGAG 1151 CTCTCTAT C CCATTCTC 1152 Cystic fibrosis ATATTTGCACATGCAACTTATTGGTCCCACTTTTTATTCTTTTG 1153 Gtu60Term CAGAGAATGGGATAGA G AGCTGGCTTCAAAGAAAAATCCTAA GAG to TAG ACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGA TCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGAT 1154 TTTTCTTTGAAGCCAGCT C TCTATCCCATTCTCTGCAAAAGAA TAAAAAGTGGGACCAATAAGTTGCATGTGCAAATAT GGGATAGA G AGCTGGCT 1155 AGCCAGCT C TCTATCCC 1156 Cystic fibrosis GGTCCCACTTTTTATTCTTTTGCAGAGAATGGGATAGAGAGC 1157 Pro67Leu TGGCTTCAAAGAAAAATC C TAAACTCATTAATGCCCTTCGGC CCT to CTT GATGTTTTTTCTGGAGATTTATGTTCTATGGAATCTT AAGATTCCATAGAACATAAATCTCCAGAAAAAACATCGCCGAA 1158 GGGCATTAATGAGTTTA G GATTTTTCTTTGAAGCCAGCTCTCT ATCCCATTCTCTGCAAAAGAATAAAAAGTGGGACC GAAAAATC C TAAACTCA 1159 TGAGTTTA G GAATTTTC 1160 Cystic fibrosis TGCAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCT 1161 Arg74Trp AAACTCATTAATGCCCTT C GGCGATGTTTTTTCTGGAGATTTA CGG to TGG TGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGA TCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAATCT 1162 CCAGAAAAAACATCGCC G AAGGGCATTAATGAGTTTAGGATT TTTCTTTGAAGCCAGCTCTCTATCCCATTCTCTGCA ATGCCCTT C GGCGATGT 1163 ACATCGCC G AAGGGCAT 1164 Congenital absence of GAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAAC 1165 vas deferens TCATTAATGCCCTTCGGC G ATGTTTTTTCTGGAGATTTTATGTT ARG75GLN CTATGGAATCTTTTTATATTTAGGGGTAAGGATCTC CGA to CAA GAGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAA 1166 ATCTCCAGAAAAAACAT C GCCGAAGGGCATTAATGAGTTTAG GATTTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTC CCTTCGGC G ATGTTTTT 1167 AAAAACAT C GCCGAAGG 1168 Cystic fibrosis GAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAAC 1169 Arg75Leu TCATTAATGCCCTTCGGC G ATGTTTTTTCTGGAGATTTTATGTT CGA to CTA CTATGGAATCTTTTTATATTAGGGGTAAGGATCTC GAGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAA 1170 ATCTCCAGAAAAAACAT C GCCGAAGGGCATTAATGAGTTTAG GATTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTC CCTTCGGC G ATGTTTTT 1171 AAAAACAT C GCCGAAGG 1172 Cystic fibrosis AGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAA 1173 Arg75Term CTCATTAATGCCCTTCGG C GATGTTTTTTCTGGAGATTTATGT CGA to TGA TCTATGGAATCTTTTTATATTTAGGGGTAAGGATCT AGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAA 1174 TCTCCAGAAAAAACATC G CCGAAGGGCATTAATGAGTTTTAGG ATTTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTCT CCCTTCGG C GATGTTTT 1175 AAAACATC G CCGAAGGG 1176 Cystic fibrosis ATTAAATCCTAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTG 1177 Gly85Glu GAGATTTATGTTCTATG G AATCTTTTTATATTTAGGGGTAAGG GGA to GAA ATCTCATTTGTACATTCATATGTATCACATAACT AGTTATGTGATACATAATGAATGTACAAATGAGATCCTTACCC 1178 CTAAATATAAAAAGATT C CATAGAACATAAATCTCCAGAAAAA ACATCGCCGAAGGGCATTAATGAGTTTAGGATTTT GTTCTATG G AATCTTTT 1179 AAAAGATT C CATAGAAC 1180 Cystic fibrosis AAAATCCTAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTG 1181 Gly85Val GAGATTTATGTTCTATG G AATCTTTTTATATTTAGGGGTAAGG GGA to GTA ATCTCATTTGTACATTCATTATGTATCACATAACT AGTTATGTGATACATAATGAATGTACAAATGAGATCCTTTACCC 1182 CTAAATATAAAAAGATT C CATAGAACATAAATCTCCAGAAAAA ACATCGCCGAAGGGCATTAATGAGTTTAGGATTTT GTTCTATG G AATCTTTT 1183 AAAAGATT C CATAGAAC 1184 Cystic fibrosis AACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTAT 1185 Leu88Ser GTTCTATGGAATCTTTTT T ATATTTAGGGGTAAGGATCTCATTT TTA to TCA GTACATTCATTATGTATCACATAACTATATGCATT AATGCATATAGTTATGTGATACATAATGAATGTACAAATGAGA 1186 TCCTTACCCCTAAATAT A AAAAGATTCCATAGAACATAAATCT CCAGAAAAAACATCGCCGAAGGGCATTAATGAGTT AATCTTTT T ATATTTAG 1187 CTAAATAT A AAAAGATT 1188 Cystic fibrosis CCTAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGAT 1189 Phe87Leu TTATGTTCTATGGAATC T TTTTATATTTAGGGGTAAGGATCTC TTT to CTT ATTTGTACATTCATTATGTATCACATAACTATATG CATATAGTTATGTGATACATAATGAATGTACAAATGAGATCCT 1190 TACCCCTAAATATAAAA A GATTCCATAGAACATAAATCTCCAG AAAAAACATCGCCGAAGGGCATTAATGAGTTTAGG ATGGAATC T TTTTATAT 1191 ATATAAAA A GATTCCAT 1192 Cystic fibrosis AACTCATTAATGCCCHCGGCGATGTTTTTTCTGGAGATTTAT 1193 Leu88Term GTTCTATGGAATCTTTT T ATATTTAGGGGTAAGGATCTCATTT TTA to TGA GTACATTCATTATGTATCACATAACTATATGCATT AATGCATATAGTTATGTGATACATAATGAATGTACAAATGAGA 1194 TCCTTACCCCTAAATAT A AAAAGATTCCATAGAACATAAATCT CCAGAAAAAACATCGCCGAAGGGCATTAATGAGTT AATCTTTT T ATATTTAG 1195 CTAAATAT A AAAAGATT 1196 Cystic fibrosis AACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTAT 1197 Leu88Term GTTCTATGGAATCTTTT T ATATTTAGGGGTAAGGATCTCATTT TTA to TAA GTACATTCATTATGTATCACATAACTATATGCATT AATGCATATAGTTATGTGATACATAATGAATGTACAAATGAGA 1198 TCCTTACCCCTAAATAT A AAAAGATTCCATAGAACATAGAATCT CCAGAAAAAACATCGCCGAAGGGCATTAATGAGTT AATCTTTT T ATATTTAG 1199 CTAAATAT A AAAAGATT 1200 Cystic fibrosis AATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATGTTCTATG 1201 Gly91Arg GAATCTTTTTATATTTA G GGGTAAGGATCTCATTTGTACATTC GGG to AGG ATTATGTATCACATAACTATATGCATTTTTGTGAT ATCACAAAAATGCATATAGTTATGTGATACATAATGAATGTAC 1202 AAATGAGATCCTTACCC C TAAATATAAAAAGATTCCATAGAAC ATAAATCTCCAGAAAAAACATCGCCGAAGGGCATT TATATTTA G GGGTAAGG 1203 CCTTACCC C TAAATATA 1204 Cystic fibrosis AATAAATGAAATTTAATTTCTCTGGTTTTCCCCTTGTGTAGGAA 1205 Gln98Arg GTCACCAAAGCAGTAC A GCCTCTCTTACTGGGAAGAATCATA CAG to CGG GCTTCCTATGACCCGGATAACAAGGAGGAACGCTC GAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATT 1206 CTTCCCAGTAAGAGAGGC T GTACTGCTTTGGTGACTTCCTAC AAAAGGGGAAAAACAGAGAAATTAAATTTCATTTATT AGCAGTAC A GCCTCTCT 1207 AGAGAGGC T GTACTGCT 1208 Cystic fibrosis AAATAAATGAAATTTAATTTCTCTGTTTTTCCCCTTTTGTAGGA 1209 Gln98Term AGTCACCAAAGCAGTA C AGCCTCTCTTACTGGGAAGAATCAT CAG-TAG AGCTTCCTATGACCCGGATAACAAGGAGGAACGCT AGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTC 1210 TTCCCAGTAAGAGAGGCT G TACTGCTTTGGTGACTTCCTACA AAAGGGGAAAAACAGAGAAATTAAATTTCATTTATTT AAGCAGTA C AGCCTCTC 1211 GAGAGGCT G TACTGCTT 1212 Cystic fibrosis CCCTTTTGTAGGAAGTCACCAAAGCAGTACAGCCTCTCTTAC 1213 Ser108Phe TGGGAAGAATCATAGCTT C CTATGACCCGGATAACAAGGAGG TCC to TTC AACGCTCTATCGCGATTTATCTAGGCATAGGCTTATG CATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTTCCTCC 1214 TTGTTATCCGGGTCATAG G AAGCTATGATTCTTCCCAGTAAG AGAGGCTGTACTGCTTTGGTGACTTCCTACAAAAGGG CATAGCTT C CTATGACC 1215 GGTCATAG G AAGCTATG 1216 Cystic fibrosis TTTTGTAGGAAGTCACCAAAGCAGTACAGCCTCTCTTACTGG 1217 Tyr109Cys GAAGAATCATAGCTTCCT A TGACCCGGATAACAAGGAGGAAC TAT to TGT GCTCTATCGCGATTATCTAGGCATAGGCTTATGCCT AGGCATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTTCC 1218 TCCTTGTTATCCGGGTCA T AGGAAGCTATGATTCTTCCCAGT AAGAGAGGCTGTACTGCTTTGGTGACTTCCTACAAAA AGCTTCCT A TGACCCGG 1219 CCGGGTCA T AGGAAGCT 1220 Cystic fibrosis TTGTAGGAAGTCACCAAAGCAGTACAGCCTCTCTTACTGGGA 1221 Asp110His AGAATCATAGCTTCCTAT G ACCCGGATAACAAGGAGGAACGC GAC to CAC TCTATCGCGATTTATCTAGGCATAGGCTTATGCCTTC GAAGGCATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTT 1222 CCTCCYTGTTATCCGGGT C ATAGGAAGCTATGATTCTTCCCA GTAAGAGAGGCTGTACTGCTTTGGTGACTTCCTACAA CTTCCTAT G ACCCGGAT 1223 ATCCGGGT C ATAGGAAG 1224 Congenital absence of AGGAAGTCACCAAAGCAGTACAGCCTCTCTTACTGGGAAGAA 1225 vas deferens TCATAGCTTCCTATGACC C GGATAACAAGGAGGAACGCTCTA Pro111Leu TCGCGATTTATCTAGGCATAGGCTTATGCCTTCTTCT CCG to CTG AAGAGAAGGCATAAGCCTATGCCTAGATAAATCGCGATAGAG 1226 CGTTCCTCCTTGTTATCC G GGTCATAGGAAGCTATGATTCTT CCCAGTAAGAGAGGCTGTACTGCTTTGGTGACTTCCT CTATGACC C GGATAACA 1227 TGTTATCC G GGTCATAG 1228 Cystic fibrosis GTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGAC 1229 Arg117Cys CCGGATAACAAGGAGGAA C GCTCTATCGCGATTTATCTAGGC CGC to TGC ATAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGC GCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCTA 1230 GATAAATCGCGATAGAGC G TTCCTCCTTGTTATCCGGGTCAT AGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTAC AGGAGGAA C GCTCTATC 1231 GATAGAGC G TTCCTCCT 1232 Cystic fibrosis TACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGACC 1233 Arg117His CGGATAACAAGGAGGAAC G CTCTATCGCGATTTATCTAGGCA CGC to CAC TAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGCT AGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCT 1234 AGATAAATCGCGATAGAG C GTTCCTCCTTGTTATCCGGGTCA TAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTA GGAGGAAC G CTCTATCG 1235 CGATAGAG C GTTCCTCC 1236 Cystic fibrosis TACAGCCTCTCGTACTGGGAAGAATCATAGCTTCCTATGACC 1237 Arg117Leu CGGATAACAAGGAGGAAC G CTCTATCGCGATTTATCTAGGCA CGC to CTC TAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGCT AGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCT 1238 AGATAAATCGCGATAGAG C GTTCCTCCTTGTTATCCGGGTCA TAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTA GGAGGAAC G CTCTATCG 1239 CGATAGAG C GTTCCTCC 1240 Cystic fibrosis TACAGCCTCTCTTTACTGGGAAGAATCATAGCTTCCTATGACC 1241 Arg117Pro CGGATAACAAGGAGGAAC G CTCTATCGCGATTTATCTAGGCA CGC to CCC TAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGCT AGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCT 1242 AGATAAATCGCGATAGAG C GTTCCTCCTTGTTATCCGGGTCA TAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTA GGAGGAAC G CTCTATCG 1243 CGATAGAG C GTTCCTCC 1244 Cystic fibrosis CTCTTACTGGGAAGAATCATAGCTTCCTATGACCCGGATAAC 1245 Ala120Thr AAGGAGGAACGCTCTATC G CGATTTATCTAGGCATAGGCTTA GCG-ACG TGCCTTCTCTTTATTGTGAGGACACTGCTCCTACACC GGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAGGCATAAG 1246 CCTATGCCTAGATAAATCG C GATAGAGCGTTCCTCCTTGTTA TCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAG GCTCTATC G CGATTTAT 1247 ATAAATCG C GATAGAGC 1248 Cystic fibrosis GGGAAGAATCATAGCTTCCTATGACCCGGATAACAAGGAGGA 1249 Tyr122Term ACGCTCTATCGCGATTTA T CTAGGCATAGGCTTATGCCTTCT TAT to TAA CTTTATTGTGAGGACACTGCTCCTACACCCAGCCATT AATGGCTGGGTGTAGGAGCAGTGTCCTCACAATAAAGAGAA 1250 GGCATAAGCCTATGCCTAG A TAAATCGCGATAGAGCGTTTCCT CCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCC GCGATTTA T CTAGGCAT 1251 ATGCCTAG A TAAATCGC 1252 Cystic fibrosis TAGCTTCCTATGACCCGGATAACAAGGAGGAACGCTCTATCG 1253 Gly126Asp CGATTTATCTAGGCATAG G CTTATGCCTTCTCTTTATTGTGAG GGC-GAC GACACTGCTCCTACACCCAGCCATTTTTGGCCTTCA TGAAGGCCAAAAATGGCTGGGTGTAGGAGCAGTGTCCTCAC 1254 AATAAAGAGAAGGCATAAG C CTATGCCTAGATAAATCGCGAT AGAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTA AGGCATAG G CTTATGCC 1255 GGCATAAG C CTATGCCT 1256 Cystic fibrosis TCGCGATTTATCTAGGCATAGGCTTATGCCTTCTCTTTATTGT 1257 Hist139Arg GAGGACACTGCTCCTAC A CCCAGCCATTTTTGGCCTTCATCA CAC to CGC CATTGGAATGCAGATGAGAATAGCTATGTTTAGTTT AAACTAAACATAGCTATTCTCATCTGCATTCCAATGTGATGAA 1258 GGCCAAAAATGGCTGGG T GTAGGAGCAGTGTCCTCACAATA AAGAGAAGGCATAAGCCTATGCCTAGATAAATCGCGA GCTCCTAC A CCCAGCCA 1259 TGGCTGGG T GTAGGAGC 1260 Cystic fibrosis TTTATCTAGGCATAGGCTTATGCCTTCTCTTTATTGTGAGGAC 1261 Ala141Asp ACTGCTCCTACACCCAG C CATTTTTGGCCTTCATCACATTGG GCC to GAC AATGCAGATGAGAATAGCTATGTTTAGTTTGATTTA TAAATCAAACTAAACATAGCTATTCTCATCTGCATTCCAATGT 1262 GATGAAGGCCAAAAATG G CTGGGTGTAGGAGCAGTGTCCTC ACAATAAAGAGAAGGCATAAGCCTATGCCTAGATAAA ACACCCAG C CATTTTTG 1263 CAAAAATG G CTGGGTGT 1264 Cystic fibrosis GCCTTCTCTTTATTGTGAGGACACTGCTCCTACACCCAGCCA 1265 lle148Thr TTTTTGGCCTTCA T CACATTGGAATGCAGATGAGAATAGCTAT ATT to ACT GTTAGTTTGATTTATAAGAAGGTAATACTTCCTTG CAAGGAAGTATTACCTTCTTATAAATCAAACTAAACATAGCTA 1266 TTCTCATCTGCATTCCA A TGTGATGAAGGCCAAAAATGGCTG GGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAGGC TCATCACA T TGGAATGC 1267 GCATTCCA A TGTGATGA 1268 Cystic fibrosis CTTCTCGTTATTGTGAGGACACTGCTCCTACACCCAGCCATTT 1269 Gly149Arg TTGGCCTTCATCACATT G GAATGCAGATGAGAATAGCTATGTT GGA to AGA TAGTTTGATTATAAGAAGGTAATACTTCCTTGCA TGCAAGGAAGTATTACCTTCTTATAAATCAAACTAAACATAGC 1270 TATTCTCATCTGCATTC C AATGTGATGAAGGCCAAAAATGGCT GGGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAG ATCACATT G GAATGCAG 1271 CTGCATTC C AATGTGAT 1272 Cystic fibrosis TTTATTGTGAGGACACTGCTCCTACACCCAGCCATTTTTGGC 1273 Gln1511Term CTTCATCACATTGGAATG C AGATGAGAATAGCTATGGTTAGTT CAG to TAG TGATTTATAAGAAGGTAATACTTCCTTGCACAGGCC GGCCTGTGCAAGGAAGTATTACCTTCTTATAAATCAAACTAAA 1274 CATAGCTATTCTCATCT G CATTCCAATGTGATGAAGGCCAAAA ATGGCTGGGTGTAGGAGCAGTGTCCTCACAATAAA TTGGAATG C AGATGAGA 1275 TCTCATCT G CATTCCAA 1276 Cystic fibrosis AATATATTTGTATTTTGTTTGTTGAAATTATCTAACTTTCCATTT 1277 Lys166Glu TTCTTTTAGACTTTA A AGCTGTCAAGCCGTGTTCTAGATAAAA AAG-GAG TAAGTATTGGACAACTTGTTAGTCTCCTTTCCA TGGAAAGGAGACTAACAAGTTGTCCAATACTTATTTTATCTAG 1278 AACACGGCTTGACAGCT T TAAAGTCTAAAAGAAAAATGGAAA GTTAGATAATTTCAACAAACAAAATACAAATATATT AGACTTTA A AGCTGTCA 1279 TGACAGCT T TAAAGTCT 1280 Cystic fibrosis TTATCTAACTTTCCATTTTTCTTTTAGACTTTAAAGCTGTCAAG 1281 lle175Val CCGTGTTCTAGATAAA A TAAGTATTGGACAACTTGTTAGTCTC ATA-GTA CTTTCCAACAACCTGAACAAATTTGATGAAGTAT ATACTTCATCAAATTTGTTCAGGTTGTTGGAAAGGAGACTAAC 1282 AAGTTGTCCAATACTTA T TTTATCTAGAACACGGCTTGACAGC TTTAAAGTCTAAAAGAAAAATGGAAAGTTAGATAA TAGATAAA A TAAGTATT 1283 AATACTTA T TTTATCTA 1284 Cystic fibrosis TTTCCATTTTTCTTTTAGACTTTAAAGCTGTCAAGCCGTGTTCT 1285 Gly178Arg AGATAAAATAAGTATT G GACAACTTGTTAGTCTCCTTTCCAAC GGA to AGA AACCTGAACAAATTTGATGAAGTATGTACCTATT AATAGGTACATACTTCATCAAATTTGTTCAGGTTGTTGGAAAG 1286 GAGACTAACAAGTTGTC C AATACTTATTTTATCTAGAACACGG CTTGACAGCTTTAAAGTCTAAAAGAAAAATGGAAA TAAGTATT G GACAACTT 1287 AAGTTGTC C AATACTTA 1288 Cystic fibrosis AAGATACAATGACACCTGTTTTTGCTGTGCTTTTATTTTCCAG 1289 His199Gln GGACTTGCATTGGCACA T TTCGTGTGGATCGCTCCTTTGCAA CAT to CAG GTGGCACTCCTCATGGGGCTAATCTGGGAGTTGTTA TAACAACTCCCAGATTAGCCCCATGAGGAGTGCCACTTGCAA 1290 AGGAGCGATCCACACGAA A TGTGCCAATGCAAGTCCCTGGA AAATAAAAGCACAGCAAAAACAGGTGTCATTGTATCTT TTGGCACA T TTCGTGTG 1291 CACACGAA A TGTGCCAA 1292 Cystic fibrosis GGAAGATACAATGACACCTGTTTTTGCTGTGCTTTTATTTTCC 1293 His199Tyr AGGGACTTGCATTGGCA C ATTTCGTGTGGATCGCTCCTTTGC CAT to TAT AAGTGGCACTCCTCATGGGGCTAATCTGGGAGTTGT ACAACTCCCAGATTAGCCCCATGAGGAGTGCCACTTGCAAAG 1294 GAGCGATCCACACGAAAT G TGCCAATGCAAGTCCCTGGAAA ATAAAAGCACAGCAAAAACAGGTGTCATTGTATCTTCC CATTGGCA C ATTTCGTG 1295 CACGAAAT G TGCCAATG 1296 Cystic fibrosis TGTTTTTGCTGTGCTTTATTTTCCAGGGACTTGCATTGGCAC 1297 Pro205Ser ATTTCGTGTGGATCGCT C CTTTGCAAGTGGCACTCCTCATGG CCT to TCT GGCTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCT AGAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCCCATG 1298 AGGAGTGCCACTTGCAAAG G AGCGATCCACACGAAATGTGC CAATGCAAGTCCCTGGAAAATAAAAGCACAGCAAAAACA GGATCGCT C CTTTGCAA 1299 TTGCAAAG G AGCGATCC 1300 Cystic fibrosis TTTGCTGTGCTTTATTTTCCAGGGACTTGCATTGGCACATTT 1301 Leu206Trp CGTGTGGATCGCTCCTT T GCAAGTGGCACTCCTCATGGGGC TTG to TGG TAATCTGGGAGTTGTTACAGGCGTCTGCCTTCTGTGG CCACAGAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCC 1302 CATGAGGAGTGCCACTTGC A AAGGAGCGATCCACACGAAAT GTGCCAATGCAAGTCCCTGGAAAATAAAAGCACAGCAAA CGCTCCTT T GCAAGTGG 1303 CCACTTGC A AAGGAGCG 1304 Cystic fibrosis TTCGTGTGGATCGCTCCTTTGCAAGTGGCACTCCTCATGGG 1305 Gln220Term GCTAATCTGGGAGTTGTTA C AGGCGTCTGCCTTCTGTGGACT CAG to TAG TGGTTTCCTGATAGTCCTTGCCCTTTTTCAGGCTGGGC GCCCAGCCTGAAAAAGGGCAAGGACTATCAGGAAACCAAGT 1306 CCACAGAAGGCAGACGCCT G TAACAACTCCCAGATTAGCCC CATGAGGAGTGCCACTTGCAAAGGAGCGATCCACACGAA AGTTGTTA C AGGCGTCT 1307 AGACGCCT G TAACAACT 1308 Cystic fibrosis CCTTTGCAAGTGGCACTCCTCATGGGGCTAATCTGGGAGTT 1309 Cys225Arg GTTACAGGCGTCTGCCTTC T GTGGACTTGGTTTCCTGATAGT TGT-CGT CCTTGCCCTTTTTCAGGCTGGGCTAGGGAGAATGATGA TCATCATTCTCCCTAGCCCAGCCTGAAAAAGGGCAAGGACTA 1310 TCAGGAAACCAAGTCCAC A GAAGGCAGACGCCTGTAACAAC TCCCAGATTAGCCCCATGAGGAGTGCCACTTGCAAAGG CTGCCTTC T GTGGACTT 1311 AAGTCCAC A GAAGGCAG 1312 Cystic fibrosis TGGGGCTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCTGT 1313 Val232Asp GGACTTGGTTTCCTGATAG T CCTTGCCCTTTTTCAGGCTGGG GTC to GAC CTAGGGAGAATGATGATGAAGTACAGGTAGCAACCTAT ATAGGTTGCTACCTGTACTTCATCATCATTCTCCCTAGCCCA 1314 GCCTGAAAAAGGGCAAGG A CTATCAGGAAACCAAGTCCACA GAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCCCA CCTGATAG T CCTTGCCC 1315 GGGCAAGG A CTATCAGG 1316 Cystic fibrosis GTTACAGGCGTCTGCCTTCTGTGGACTTGGTTTCCTGATAGT 1317 Gly239Arg CCTTGCCCTTTTTCAGGC T GGGCTAGGGAGAATGATGATGAA GGG to AGG GTACAGGTAGCAACCTATTTTCATAACTTGAAAGTTT AAACTTTCAAGTTATGAAAATAGGTTGCTACCTGTACTTCATC 1318 ATCATTCTCCCTAGCCC A GCCTGAAAATTAGGGCAAGGACTATC AGGAAACCAAGTCCACAGAAGGCAGACGCCTGTAAC TTTCAGGC T GGGCTAGG 1319 CCTAGCCC A GCCTGAAA 1320

EXAMPLE 10 Cyclin-dependent Kinase Inhibitor 2A—CDKN2A

The human CDKN2A gene was also designated MTS-1 for multiple tumor suppressor-1 and has been implicated in multiple cancers including, for example, malignant melanoma. Malignant melanoma is a cutaneous neoplasm of melanocytes. Melanomas generally have features of asymmetry, irregular border, variegated color, and diameter greater than 6 mm. The precise cause of melanoma is unknown, but sunlight and heredity are risk factors. Melanoma has been increasing during the past few decades.

The CDKN2A gene has been found to be homozygously deleted at high frequency in cell lines derived from tumors of lung, breast, brain, bone, skin, bladder, kidney, ovary, and lymphocyte. Melanoma cell lines carried at least one copy of CDKN2A in combination with a deleted allele. Melanoma cell lines that carried at least 1 copy of CDKN2A frequently showed nonsense, missense, or frameshift mutations in the gene. Thus, CDKN2A may rival p53 (see Example 5) in the universality of its involvement in tumorigenesis. The attached table discloses the correcting oligonucleotide base sequences for the CDKN2A oligonucleotides of the invention.

TABLE 17 CDKN2A Mutations and Genome-Correcting Oligos SEQ ID Clinical Phenotype & Correcting Oligos NO: Melanoma GGGCGGCGGGGAGCAGCATGGAGCCGGCGGCGGGGAGCAG 1321 Trp15Term CATGGAGCCTTCGGCTGACT G CTGGCCACGGCCGCGGCCC TGG–TAG GGGGTCGGGTAGAGGAGGTGCGGGCGCTGCTGGAGGCGGG CCCGCCTCCAGCAGCGCCCGCACCTCCTCTACCCGACCCCG 1322 GGCCGCGGCCGTGGCCAGC C AGTCAGCCGAAGGCTCCATGC TGCTCCCCGCCGCCGGCTCCATGCTGCTCCCCGCCGCCC GGCTGACT G GCTGGCCA 1323 TGGCCAGC C AGTCAGCC 1324 Melanoma CGGCGGGGAGCAGCATGGAGCCGGCGGCGGGGAGCAGCAT 1325 Leu16Pro GGAGCCTTCGGCTGACTGGCTGGCCACGGCCGCGGCCCGG CTG–CCG GGTCGGGTAGAGGAGGTGCGGGCGCTGCTGGAGGCGGGGG C GCCCCCGCCTCCAGCAGCGCCCGCACCTCCTCTACCGACC 1326 CCGGGCCGCGGCCGTGGCCAGCC A GTCAGCCGAAGGCTCC ATGCTGCTCCCCGCCGCCGGCTCCATGCTGCTCCCCGCCG TGACTGGC T GGCCACGG 1327 CCGTGGCC A GCCAGTCA 1328 Melanoma CGGCGGCGGGGAGCAGCATGGAGCCTTCGGCTGACTGGCTG 1329 Gly23Asp GCCACGGCCGCGGCCCGGG G TCGGGTAGAGGAGGTGCGGG CTG–CCG CGCTGCTGGAGGCGGGGGCGCTGCCCAACGCACCGAATAG CTATTCGGTGCGTTGGGCAGCGCCCCCGCCTCCAGCAGCGC 1330 CCGCACCTCCTCTACCCGA C CCCGGGCCGCGGCCGTGGCCA GCCAGTCAGCCGAAGGCTCCATGCTGCTCCCCGCCGCCG GGCCCGGG G TCGGGTAG 1331 CTACCCGA C CCCGGGCC 1332 Melanoma CGGCGGGGAGCAGCATGGAGCCTTCGGCTGACTGGCTGGCC 1333 Arg24Pro ACGGCCGCGGCCCGGGGTC G GGTAGAGGAGGTGCGGGCGC CGG–CCG TGCTGGAGGCGGGGGCGCTGCCCAACGCACCGAATAGTTA TAACTATTCGGTGCGTTGGGCAGCGCCCCCGCCTCCAGCAGC 1334 GCCCGCACCTCCTCTACC C GACCCCGGGCCGCGGCCGTGGC CAGCCAGTCAGCCGAAGGCTCCATGCTGCTCCCCGCCG CCGGGGTC G GGTAGAGG 1335 CCTCTACC C GACCCCGG 1336 Melanoma CGGCTGACTGGCTGGCCACGGCCGCGGCCCGGGGTCGGGT 1337 Leu32Pro AGAGGAGGTGCGGGCGCTGC T GGAGGCGGGGGCGCTGCCC CTG–CCG AACGCACCGAATAGTTACGGTCGGAGGCCGATCCAGGTGGG CCCACCTGGATCGGCCTCCGACCGTAACTATTCGGTGCGTTG 1338 GGCAGCGCCCCCGCCTCCAGC A GCGCCCGCACCTCCTCTAC CCGACCCCGGGCCGCGGCCGTGGCCAGCCAGTCAGCCG GGCGCTGC T GGAGGCGG 1339 CCGCCTCC A GCAGCGCC 1340 Melanoma GGCTGGCCACGGCCGCGGCCCGGGGTCGGGTAGAGGAGGT 1341 Gly35Ala GCGGGCGCTGCTGGAGGCGG G GGCGCTGCCCAACGCACCG GGG–GCG AATAGTTACGGTCGGAGGCCGATCCAGGTGGGTAGAGGGTC GACCCTCTACCCACCTGGATCGGCCTCCGACCGTAACTATTC 1342 GGTGCGTTGGGCAGCGCC C CCGCCTCCAGCAGCGCCCGCAC CTCCTCTACCCGACCCCGGGCCGCGGCCGTGGCCAGCC GGAGGCGG G GGCGCTGC 1343 GCAGCGCC C CCGCCTCC 1344 Melanoma GGTAGAGGAGGTGCGGGCGCTGCTGGAGGCGGGGGCGCTG 1345 Tyr44Term CCCAACGCACCGAATAGTTA C GGTCGGAGGCCGATCCAGGTG TACg–TAA GGTAGAGGGTCTGCAGCGGGAGCAGGGGATGGCGGGCGA TCGCCCGCCATCCCCTGCTCCCGCTGCAGACCCTCTACCCAC 1346 CTGGATCGGCCTCCGACC G TAACTATTCGGTGCGTTGGGCAG CGCCCCCGCCTCCAGCAGCGCCCGCACCTCCTCTACC AATAGTTA C GGTCGGAG 1346 CTCCGACC G TAACTATT 1348 Melanoma TCTCCCATACCTGCCCCCACCCTGGCTCTGACCACTCTGCTC 1349 Met53IIe TCTCTGGCAGGTCATGAT G ATGGGCAGCGCCCGCGTGGCGG ATGa–ATC AGCTGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCA TGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCTCCG 1350 CCACGCGGGCGCTGCCCAT C ATCATGACCTGCCAGAGAGAG CAGAGTGGTCAGAGCCAGGGTGGGGGCAGGTATGGGAGA GTCATGAT G ATGGGCAG 1351 CTGCCCAT C ATCATGAC 1352 Melanoma CCCATACCTGCCCCCACCCTGGCTCTGACACTCTGCTCTCT 1353 Met54IIe CTGGCAGGTCATGATGAT G GGCAGCGCCCGCGTGGCGGAGC ATGg–ATV TGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCAGAC GTCTGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCT 1354 CCGCCACGCGGGCGCTGCC C ATCATCATGACCTGCCAGAGA GAGCAGAGTGGTCAGAGCCAGGGTGGGGGCAGGTATGGG ATGATGAT G GGCAGCGC 1355 GCGCTGCC C ATCATCAT 1356 Melanoma GCCGGCCCCACCCTGGCTCTGACCATTCTGTTCTCTCTGGC 1357 Ser56IIe AGGTCATGATGATGGGCA G CGCCCGAGTGGCGGAGCTGCTG AGC–ATC CTGCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGC GCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCA 1358 GCAGCTCCGCCACTCGGGCG C TGCCCATCATCATGACCTGCC AGAGAGAACAGAATGGTCAGAGCCAGGGTGGGGGCCGGC GATGGGCA G CGCCCGAG 1359 CTCGGGCG C TGCCCATC 1360 Melanoma GGCCCCCACCCTGGCTCTGACCATTCTGTTCTCTCTGGCAGG 1361 Ala57Val TCATGATGATGGGCAGCG C CCGAGTGGCGGAGCTGCTGCTG GCC–GTC CTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCAC GTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCA 1362 GCAGCAGCTCCGCCACTCGG G CGCTGCCCATCATCATGACCT GCCAGAGAGAACAGAATGGTCAGAGCCAGGGTGGGGGCC GGGCAGCG C CCGAGTGG 1363 CCACTCGG G CGCTGCCC 1364 Melanoma CCCCCACCCTGGCTCTGACCATTCTGTTCTCTCTGGCAGGTC 1365 Arg58Term ATGATGATGGGCAGCGCC C GAGTGGCGGAGCTGCTGCTGCT cCGA–TGA CCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTC GAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAG 1366 CAGCAGCAGCTCCGCCACTC G GGCGCTGCCCATCATCATGAC CTGCCAGAGAGAACAGAATGGTCAGAGCCAGGGTGGGGG GCAGCGCC C GAGTGGCG 1367 CGCCACTC G GGCGCTGC 1368 Melanoma CACCCTGGCTCTGACCATTCTGTTCTCTCTGGCAGGTCATGAT 1369 Val59Gly GATGGGCAGCGCCCGAG T GGCGGAGCTGCTGCTGCTCCACG GTG–GGG GCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTCAC GTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTG 1370 GAGCAGCAGCAGCTCCGCC A CTCGGGCGCTGCCCATCATCA TGACCTGCCAGAGAGAACAGAATGGTCAGAGCCAGGGTG CGCCCGAG T GGCGGAGC 1371 GCTCCGCC A CTCGGGCG 1372 Melanoma TCTGACCACTCTGCTCTCTCTGGCAGGTCATGATGATGGGCA 1373 Leu62Pro GCGCCCGCGTGGCGGAGC T GCTGCTGCTCCACGGCGCGGA CTG–CCG GCCCAACTGCGCAGACCCTGCCACTCTCACCCGACCGGT ACCGGTCGGGTGAGAGTGGCAGGGTCTGCGCAGTTGGGCTC 1374 CGCGCCGTGGAGCAGCAGC A GCTCCGCCACGCGGGCGCTG CCCATCATCATGACCTGCCAGAGAGAGCAGAGTGGTCAGA GGCGGAGC T GCTGCTGC 1375 GCAGCAGC A GCTCCGCC 1376 Melanoma TCTGGCAGGTCATGATGATGGGCAGCGCCCGCGTGGCGGAG 1377 Ala68Val CTGCTGCTGCTCCACGGCG CGGAGCCCAACTGCGCAGACCC GCG–GTG TGCCACTCTCACCCGACCGGTGCATGATGCTGCCCGGGA TCCCGGGCAGCATCATGCACCGGTCGGGTGAGAGTGGCAGG 1378 GTCTGCGCAGTTGGGCTCC G CGCCGTGGAGCAGCAGCAGCT CCGCCACGCGGGCGCTGCCCATCATCATGACCTGCCAGA CCACGGCG C GGAGCCCA 1379 TGGGCTCC G CGCCGTGG 1380 Melanoma CATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTGC 1381 Asn71Lys TCCACGGCGCGGAGCCCAA C TGCGCCGACCCCGCCACTCTC AACt–AAA ACCCGACCCGTGCACGACGCTGCCCGGGAGGGCTTCCTG CAGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGA 1382 GAGTGGCGGGGTCGGCGCA G TTGGGCTCCGCGCCGTGGAG CAGCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCATG GAGCCCAA C TGCGCCGA 1383 TCGGCGCA G TTGGGCTC 1384 Melanoma TCATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTG 1385 Asn71Ser CTCCACGGCGCGGAGCCCA A CTGCGCCGACCCCGCCACTCT AAC–AGC CACCCGACCCGTGCACGACGCTGCCCGGGAGGGCTTCCT AGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGAG 1386 AGTGGCGGGGTCGGCGCAG T TGGGCTCCGCGCCGTGGAGCA GCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCATGA GGAGCCCA A CTGCGCCG 1387 CGGCGCAG T TGGGCTCC 1388 Melanoma AGCTGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCCGAC 1389 Pro81Leu CCGCCACTCTCACCCGACC C GTGCACGACGCTGCCCGGGA CCC–CTC GGGCTTCCTGGACACGCTGGTGGTGCTGCACCGGGCCGG CCGGCCCGGTGCAGCACCACCAGCGTGTCCAGGAAGCCCTC 1390 CCGGGCAGCGTCGTGCACG G GTCGGGTGAGAGTGGCGGGG TCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCT CACCCGAC C CGTGCACG 1391 CGTGCACG G GTCGGGTG 1392 Melanoma CTGCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCAC 1393 Asp84Tyr TCTCACCCGACCCGTGCACGAC G CTGCCCGGGAGGGCTTCC cGAC–TAC TGGACACGCTGGTGGTGCTGCACCGGGCCGGGGCGCGGC GCCGCGCCCCGGCCCGGTGCAGCACCACCAGCGTGTCCAGG 1394 AAGCCCTCCCGGGCAGCGT C GTGCACGGGTCGGGTGAGAGT GGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAG CCGTGCAC G ACGCTGCC 1395 GGCAGCGT C GTGCACGG 1396 Melanoma CTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCT 1397 Ala85Thr CACCCGACCCGTGCACGAC G CTGCCCGGGAGGGCTTCCTGG cGCT–ACT ACACGCTGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGG CCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAGCGTGTCC 1398 AGGAAGCCCTCCCGGGCAG C GTCGTGCACGGGTCGGGTGAG AGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAG TGCACGAC G CTGCCCGG 1399 CCGGGCAG C GTCGTGCA 1400 Melanoma GCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTCACCCGA 1401 Arg87Pro CCCGTGCACGACGCTGCCC G GGAGGGCTTCCTGGACACGCT CGG–CCG GGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGACGTGCG CGCACGTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAG 1402 CGTGTCCAGGAAGCCCTCC C GGGCAGCGTCGTGCACGGGTC GGGTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGC CGCTGCCC G GGAGGGCT 1403 AGCCCTCC C GGGCAGCG 1404 Melanoma GGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTCACCCG 1405 Arg87Trp ACCCGTGCACGACGCTGCC C GGGAGGGCTTCCTGGACACGC cCGG–TGG TGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGACGTGC GCACGTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAGC 1406 GTGTCCAGGAAGCCCTCCC G GGCAGCGTCGTGCACGGGTCG GGTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCC ACGCTGCC C GGGAGGGC 1407 GCCCTCCC G GGCAGCGT 1408 Melanoma CTCTCACCCGACCGGTGCATGATGCTGCCCGGGAGGGCTTC 1409 Leu97Arg CTGGACACGCTGGTGGTGC T GCACCGGGCCGGGGCGCGGCT CTG–CGG GGACGTGCGCGATGCCTGGGGTCGTCTGCCCGTGGACTT AAGTCCACGGGCAGACGACCCCAGGCATCGCGCACGTCCAG 1410 CCGCGCCCCGGGCCGGTGCAGC A CCACCAGCGTGTCCAGGA AGCCCTCCCGGGCAGCATCATGCACCGGTCGGGTGAGAG GGTGGTGC T GCACCGGG 1411 CCCGGTGC A GCACCACC 1412 Melanoma CCCGACCGGTGCATGATGCTGCCCGGGAGGGCTTCCTGGAC 1413 Arg99Pro ACGCTGGTGGTGCTGCACC G GGCCGGGGCGCGGCTGGACG CGG–CCG TGCGCGATGCCTGGGGTCGTCTGCCCGTGGACTTGGCCGA TCGGCCAAGTCCACGGGCAGACGACCCCAGGCATCGCGCAC 1414 GTCCAGCCGCGCCCCGGCC C GGTGCAGCACCACCAGCGTGT CCAGGAAGCCCTCCCGGGCAGCATCATGCACCGGTCGGG GCTGCACC G GGCCGGGG 1415 CCCCGGCC C GGTGCAGC 1416 Melanoma CCGGTGCATGATGCTGCCCGGGAGGGCTTCCTGGACACGCT 1417 Gly101Trp GGTGGTGCTGCACCGGGCC G GGGCGCGGCTGGACGTGCGC cGGG–TGG GATGCCTGGGGTCGTCTGCCCGTGGACTTGGCCGAGGAGC GCTCCTCGGCCAAGTCCACGGGCAGACGACCCCAGGCATCG 1418 CGCACGTCCAGCCGCGCCC C GGCCCGGTGCAGCACCACCAG CGTGTCCAGGAAGCCCTCCCGGGCAGCATCATGCACCGG ACCGGGCC G GGGCGCGG 1419 CCGCGCCC C GGCCCGGT 1420 Melanoma CGGGAGGGCTTCCTGGACACGCTGGTGGTGCTGCACCGGGC 1421 Arg107Cys CGGGGCGCGGCTGGACGTG C GCGATGCCTGGGGTCGTCTGC gCGC–TGC CCGTGGACTTGGCCGAGGAGCGGGGCCACCGCGACGTTG CAACGTCGCGGTGGCCCCGCTCCTCGGCCAAGTCCACGGGC 1422 AGACGACCCCAGGCATCGC G CACGTCCAGCCGCGCCCCGGC CCGGTGCAGCACCACCAGCGTGTCCAGGAAGCCCTCCCG TGGACGTG C GCGATGCC 1423 GGCATCGC G CACGTCCA 1424 Melanoma CACCGGGCCGGGGCGCGGCTGGACGTGCGCGATGCCTGGG 1425 Ala118Thr GCCGTCTGCCCGTGGACCTG G CTGAGGAGCTGGGCCATCGC gGCT–ACT GATGTCGCACGGTACCTGCGCGCGGCTGCGGGGGGCACCA TGGTGCCCCCCGCAGCCGCGCGCAGGTACCGTGCGACATCG 1426 CGATGGCCCAGCTCCTCAG C CAGGTCCACGGGCAGACGGCC CCAGGCATCGCGCACGTCCAGCCGCGCCCCGGCCCGGTG TGGACCTG G CTGAGGAG 1427 CTCCTCAG C CAGGTCCA 1428 Melanoma TGCGCGATGCCTGGGGCCGTCTGCCCGTGGACCTGGCTGAG 1429 Val126Asp GAGCTGGGCCATCGCGATG T CGCACGGTACCTGCGCGCGGC GTC–GAC TGCGGGGGGCACCAGAGGCAGTAACCATGCCCGCATAGA TCTATGCGGGCATGGTTACTGCCTCTGGTGCCCCCCGCAGCC 1430 GCGCGCAGGTACCGTGCG A CATCGCGATGGCCCAGCTCCTC AGCCAGGTCCACGGGCAGACGGCCCCAGGCATCGCGCA TCGCGATG T CGCACGGT 1431 ACCGTGCG A CATCGCGA 1432

EXAMPLE 11 Adenomatous Polyposis of the Colon—APC

Adenomatous polyposis of the colon is characterized by adenomatous polyps of the colon and rectum; in extreme cases the bowel is carpeted with a myriad of polyps. This is a viciously premalignant disease with one or more polyps progressing through dysplasia to malignancy in untreated gene carriers with a median age at diagnosis of 40 years.

Mutations in the APC gene are an initiating event for both familial and sporadic colorectal tumorigenesis and many alleles of the APC gene have been identified. Carcinoma may arise at any age from late childhood through the seventh decade with presenting features including, for example, weight loss and inanition, bowel obstruction, or bloody diarrhea. Cases of new mutation still present in these ways but in areas with well organized registers most other gene carriers are detected. The attached table discloses the correcting oligonucleotide base sequences for the APC oligonucleotides of the invention.

TABLE 18 APC Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting oligos NO: Adenomatous polyposis GGATCTGTATCAAGCCGTTCTGGAGAGTGCAGTCCTGTTCCT 1433 coli ATGGGTTCATTTCCAAGA A GAGGGTTTGTAAATGGAAGCAGA Arg121Term GAAAGTACTGGATATTTAGAAGAACTTGAGAAAGAGA AGA-TGA TCTCTTTCTCAAGTTCTTCTAAATATCCAGTACTTTCTCTGCTT 1434 CCATTTACAAACCCTC T TCTTGGAAATGAACCCATAGGAACAG GACTGCACTCTCCAGAACGGCTTGATACAGATCC TTCCAAGA A GAGGGTTT 1435 AAACCCTC T TCTTGGAA 1436 Adenomatous polyposis AAAAAAAAAATAGGTCATTGCTTCTTGCTGATCTTGACAAAGAA 1437 coil GAAAAGGAAAAAGACT G GTATTACGCTCAACTTCAGAATCTCA Trp157Term CTAAAAGAATAGATAGTCTTCCTTTAACTGAAAA TGG-TAG TTTTCAGTTAAAGGAAGACTATCTATTCTTTTAGTGAGATTCTG 1438 AAGTTGAGCGTAATAC C AGTCTTTTTCCTTTTCTTCTTTGTCAA GATCAGCAAGAAGCAATGACCTATTTTTTTTTT AAAAGACT G GTATTACG 1439 CGTAATAC C AGTCTTTT 1440 Adenomatous polyposis AAATAGGTCATTGCTTCTTGCTGATCTTGACAAAGAAGAAAAG 1441 coli GAAAAAGACTGGTATTA C GCTCAACTTCAGAATCTCACTAAAA Tyr159Term GAATAGATAGTCTTCCTTTAACTGAAAATGTAAGT TAG-TAG ACTTACATTTTCAGTTAAAGGAAGACTATCTATTCTTTTAGTGA 1442 GATTCTGAAGTTGAGC G TAATACCAGTCTTTTTCCTTTTCTTCT TTGTCAAGATCAGCAAGAAGCAATGACCTATTT TGGTATTA C GCTCAACT 1443 AGTTGAGC G TAATACCA 1444 Adenomatous polyposis TTGCTTCTTGCTGATCTTGACAAAGAAGAAAAGGAAAAAGACT 1445 coli GGTATTACGCTCAACTT C AGAATCTCACTAAAAGAATAGATAG Gln163Term TCTTCCTTTAACTGAAAATGTAAGTAACTGGCAGT CAG-TAG ACTGCCAGTTACTTACATTTTCAGTTAAAGGAAGACTATCTATT 1446 CTTTTAGTGAGATTCT G AAGTTGAGCGTAATACCAGTCTTTTTC CTTTTCTTCTTTGTCAAGATCAGCAAGAAGCAA CTCAACTT C AGAATCTC 1447 GAGATTCT G AAGTTGAG 1448 Adenomatous polyposis CTTGACAAAGAAGAAAAGGAAAAAGACTGGTATTACGCTCAAC 1449 coli TTCAGAATCTCACTAAA A GAATAGATAGTCTTCCTTTAACTGAA Arg168Term AATGTAAGTAACTGGCAGTACAACTTATTTGAAA AGA-TGA TTTCAAATAAGTTGTACTGCCAGTTACTTACATTTTCAGTTAAA 1450 GGAAGACTATCTATTC T TTTAGTGAGATTCTGAAGTTGAGCGT AATACCAGTCTTTTTCCTTTTCTTCTTTGTCAAG TCACTAAA A GAATAGAT 1451 ATCTATTC T TTTAGTGA 1452 Adenomatous polyposis AAGAAAAGGAAAAAGACTGGTATTACGCTCAACTTCAGAATCT 1453 coli CACTAAAAGAATAGATA G TCTTCCTTTAACTGAAAATGTAAGTA Ser171Ile ACTGGCAGTACAACTTATTTGAAACTTTAATAAC AGT-ATT GTTATTAAAGTTTCAAATAAGTTGTACTGCCAGTTACTTACATT 1454 TTCAGTTAAAGGAAGA C TATCTATTCTTTTAGTGAGATTCTGAA GTTGAGCGTAATACCAGTCTTTTTCCTTTTCTT AATAGATA G TCTTCCTT 1455 AAGGAAGA C TATCTATT 1456 Adenomatous polyposis GATTAACGTAAATACAAGATATTGATACTTTTTTATTATTTGTGG 1457 coli TTTTAGTTTTCCTTA C AAACAGATATGACCAGAAGGCAATTGG Gln181Term AATATGAAGCAAGGCAAATCAGAGTTGCGATGG CAA-TAA CCATCGCAACTCTGATTTGCCTTGCTTCATATTCCAATTGCCT 1458 TCTGGTCATATCTGTTT G TAAGGAAAACTAAAACCACAAATAAT AAAAAAGTATCAATATCTTGTATTTACGTTAATC TTTCCTTA C AAACAGAT 1459 ATCTGTTT G TAAGGAAA 1460 Adenomatous polyposis CTTTTTTATTATTTGTGGTTTTAGTTTTCCTTACAAACAGATATG 1461 coli ACCAGAAGGCAATTG G AATATGAAGCAAGGCAAATCAGAGTT Glu190Term GCGATGGAAGAACAACTAGGTACCTGCCAGGATA GAA-TAA TATCCTGGCAGGTACCTAGTTGTTCTTCCATCGCAACTCTGAT 1462 TTGCCTTGCTTCATATT C CAATTGCCTTCTGGTCATATCTGTTT GTAAGGAAAACTAAAACCACAAATAATAAAAAAG GGCAATTG G AATATGAA 1463 TTCATATT C CAATTGCC 1464 Adenomatous polyposis CAATTGGAATATGAAGCAAGGCAAATCAGAGTTGCGATGGAA coli GAACAACTAGGTACCTGC C AGGATATGGAAAAACGAGCACAG Gln208Term GTAAGTTACTTGTTTCTAAGTGATAAAACAGCGAAGA CAG-TAG TCTTCGCTGTTTTATCACTTAGAAACAAGTAACTTACCTGTGCT 1466 CGTTTTTCCATATCCT G GCAGGTACCTAGTTGTTCTTCCATCG CAACTCTGATTTGCCTTGCTTCATATTCCAATTG GTACCTGC C GCAGGTAC 1467 CATATCCT G GCAGGTAC 1468 Adenomatous polyposis GCAAGGCAAATCAGAGTTGCGATGGAAGAACAACTAGGTACC 1469 coli TGCCAGGATATGGAAAAA C GAGCACAGGTAAGTTACTTGTTTC Arg213Term TAAGTGATAAAACAGCGAAGAGCTATTAGGAATAAA CGA-TGA TTTATTCCTAATAGCTCTTCGCTGTTTTATCACTTAGAAACAAG 1470 TAACTTACCTGTGCTC G TTTTTCCATATCCTGGCAGGTACCTA GTTGTTCTTCCATCGCAACTCTGATTTGCCTTGC TGGAAAAA C GAGCACAG 1471 CTGTGCTC G TTTTTCCA 1472 Adenomatous polyposis GTTTTATTTTAGCGAAGAATAGCCAGAATTCAGCAAATCGAAA 1473 coli AGGACATACTTCGTATA C GACAGCTTTTACAGTCCCAAGCAAC Arg232Term AGAAGCAGAGGTTAGTAAATTGCCTTTCTTGTTTG CGA-TGA CAAACAAGAAAGGCAATTTACTAACCTCTGCTTCTGTTGCTTG 1474 GGACTGTAAAAGCTGTC G TATACGAAGTATGTCCTTTTCGATT TGCTGAATTCTGGCTATTCTTCGCTAAAATAAAAC TTCGTATA C GACAGCTT 1475 AAGCTGTC G TATACGAA 1476 Adenomatous polyposis TTATTTTAGCGAAGAATAGCCAGAATTCAGCAAATCGAAAAGG 1477 coli ACATACTTCGTATACGA C AGCTTTTACAGTCCCAAGCAACAGA Gln233Term AGCAGAGGTTAGTAAATTGCCTTTCTTGTTTGTGG CAG-TAG CCACAAACAAGAAAGGCAATTTACTAACCTCTGCTTCTGTTGC 1478 TTGGGACTGTAAAAGCT G TCGTATACGAAGTATGTCCTTTTCG ATTTGCTGAATTCTGGCTATTCTTCGCTAAAATAA GTATACGA C AGCTTTTA 1479 TAAAAGCT G TCGTATAC 1480 Adenomatous polyposis AGAAAGCCTACACCATTTTTGCATGTACTGATGTTAACTCCAT 1481 coli CTTAACAGAGGTCATCT C CTCACAGAACAAGCATGAAACCGGCTCAC Gln247Term ATGATGCTGAGCGGCAGAATGAAGGTCAAGGAGTGG CAG-TAG CCACTCCTTGACCTTCATTCTGCCGCTCAGCATCATGTGAGC 1482 CGGTTTCATGCTTGTTCT G AGATGACCTCTGTTAAGATGGAGT TAACATCAGTACATGCAAAAATGGTGTAGGCTTTCT GGTCATCT C AGAACAAG 1483 CTTGTTCT G AGATGACC 1484 Adenomatous polyposis CAGAACAAGCATGAAACCGGCTCACATGATGCTGAGCGGCAG 1485 coli AATGAAGGTCAAGGAGTG G GAGAAATCAACATGGCAACTTCT Gly267Term GGTAATGGTCAGGTAAATAAATTATTTTATCATATTT GGA-TGA AAATATGATAAAATAATTTATTTACCTGACCATTACCAGAAGTT 1486 GCCATGTTGATTTCTC C CACTCCTTGACCTTCATTCTGCCGCT CAGCATCATGTGAGCCGGTTTCATGCTTGTTCTG AAGGAGTG G GAGAAATC 1487 GATTTCTC C CACTCCTT 1488 Adenomatous polyposis CTTCAAATAACAAAGCATTATGGTTTATGTTGATTTTATTTTTCA 1489 coli GTGCCAGCTCCTGTT G AACATCAGATCTGTCCTGCTGTGTGT Glu443Term GTTCTAATGAAACTTTCATTTGATGAAGAGCATA GAA-TAA TATGCTCTTCATCAAATGAAAGTTTCATTAGAACACACACAGCA 1490 GGACAGATCTGATGTT C AACAGGAGCTGGCACTGAAAAATAA AATCAACATAAACCATAATGCTTTGTTATTTGAAG CTCCTGTT G AACATCAG 1491 CTGATGTT C AACAGGAG 1492 Adenomatous polyposis CAGTGCCAGCTCCTGTTGAACATCAGATCTGTCCTGCTGTGT 1493 coli GTGTTCTAATGAAACTTT C ATTTGATGAAGAGCATAGACATGC SER457TER AATGAATGAACTAGGTAAGACAAAAATGTTTTTTAA TCA-TAA TTAAAAACATTTTTGTCTTACCTAGTTCATTCATTGCATGTCTA 1494 TGCTCTTCATCAAAT G AAAGTTTCATTAGAACACACACAGCAG GACAGATCTGATGTTCAACAGGAGCTGGCACTG GAAACTTT C ATTTGATG 1495 CATCAAAT G AAAGTTTC 1496 Adenomatous polyposis AGTTGTTTTATTTTAGATGATTGTCTTTTTCCTCTTGCCCTTTTT 1497 coli AAATTAGGGGGACTA C AGGCCATTGCAGAATTATTGCAAGTG Gln473Term GACTGTGAAATGTACGGGCTTACTAATGACCACT CAG-TAG AGTGGTCATTAGTAAGCCCGTACATTTCACAGTCCACTTGCAA 1498 TAATTCTGCAATGGCCT G TAGTCCCCCTAATTTAAAAAGGGCA AGAGGAAAAAGACAATCATCTAAAATAAAACAACT GGGGACTA C AGGCCATT 1499 AATGGCCT G TAGTCCCC 1500 Adenomatous polyposis TTTTAAATTAGGGGGACTACAGGCCATTGCAGAATTATTGCAA 1501 coli GTGGACTGTGAAATGTA C GGGCTTACTAATGACCACTACAGTA Tyr486Term TTACACTAAGACGATATGCTGGAATGGCTTTGACA TAC-TAG TGTCAAAGCCATTCCAGCATATCGTCTTAGTGTAATACTGTAG 1502 TGGTCATTAGTAAGCCC G TACATTTCACAGTCCACTTGCAATA ATTCTGCAATGGCCTGTAGTCCCCCTAATTTAAAA GAAATGTA C GGGCTTAC 1503 GTAAGCCC G TACATTTC 1504 Adenomatous polyposis TTGCAAGTGGACTGTGAAATGTATGGGCTTACTAATGACCACT 1505 coli ACAGTATTACACTAAGA C GATATGCTGGAATGGCTTTGACAAA Arg499Term CTTGACTTTTGGAGATGTAGCCAACAAGGTATGTT CGA-TGA AACATACCTTGTTGGCTACATCTCCAAAAGTCAAGTTTGTCAA 1506 AGCCATTCCAGCATATC G TCTTAGTGTAATACTGTAGTGGTCA TTAGTAAGCCCATACATTTCACAGTCCACTTGCAA CACTAAGA C GATATGCT 1507 AGCATATC G TCTTAGTG 1508 Adenomatous polyposis AGTGGACTGTGAAATGTATGGGCTTACTAATGACCACTACAGT 1509 coli ATTACACTAAGACGATA T GCTGGAATGGCTTTGACAAACTTGA Tyr500Term CTTTTGGAGATGTAGCCAACAAGGTATGTTTTTAT TAT-TAG ATAAAAACATACCTTGTTGGCTACATCTCCAAAAGTCAAGTTTG 1510 TCAAAGCCATTCCAGC A TATCGTCTTAGTGTAATACTGTAGTG GTCATTAGTAAGCCCATACATTTCACAGTCCACT AGACGATA T GCTGGAAT 1511 ATTCCAGC A TATCGTCT 1512 Adenomatous polyposis GACAAATTCCAACTCTAATTAGATGACCCATATTCTGTTTCTTA 1513 coli CTAGGAATCAACCCTC A AAAGCGTATTGAGTGCCTTATGGAAT Lys586Term TTGTCAGCACATTGCACTGAGAATAAAGCTGATA AAA-TAA TATCAGCTTTATTCTCAGTGCAATGTGCTGACAAATTCCATAA 1514 GGCACTCAATACGCTTT T GAGGGTTGATTCCTAGTAAGAAACA GAATATGGGTCATCTAATTAGAGTTGGAATTTGTC CAACCCTC A AAAGCGTA 1515 TACGCTTT T GAGGGTTG 1516 Adenomatous polyposis TAGATGACCCATATTCTGTTTCTTACTAGGAATCAACCCTCAAA 1517 coli AGCGTATTGAGTGCCT T ATGGAATTTGTCAGCACATTGCACTG Leu592Term AGAATAAAGCTGATATATGTGCTGTAGATGGTGC TTA-TGA GCACCATCTACAGCACATATATCAGCTTTATTCTCAGTGCAAT 1518 GTGCTGACAAATTCCAT A AGGCACTCAATACGCTTTTGAGGGT TGATTCCTAGTAAGAAACAGAATATGGGTCATCTA GAGTGCCT T ATGGAATT 1519 AATTCCAT A AGGCACTC 1520 Adenomatous polyposis ATGACCCATATTCTGTTTCTTACTAGGAATCAACCCTCAAAAG 1521 coli CGTATTGAGTGCCTTAT G GAATTTGTCAGCACATTGCACTGAG Trp593Term AATAAAGCTGATATATGTGCTGTAGATGGTGCACT TGG-TAG AGTGCACCATCTACAGCACATATATCAGCTTTATTCTCAGTGC 1522 AATGTGCTGACAAATTC C ATAAGGCACTCAATACGCTTTTGAG GGTTGATTCCTAGTAAGAAACAGAATATGGGTCAT TGCCTTAT G GAATTTGT 1523 ACAAATTC C ATAAGGCA 1524 Adenomatous polyposis TGACCCATATTCTGTTTCTTACTAGGAATCAACCCTCAAAAGC 1525 coli GTATTGAGTGCCTTATG G AATTTGTCAGCACATTGCACTGAGA Trp593Term ATAAAGCTGATATATGTGCTGTAGATGGTGCACTT TGG-TGA AAGTGCACCATCTACAGCACATATATCAGCTTTATTCTCAGTG 1526 CAATGTGCTGACAAATT C CATAAGGCACTCAATACGCTTTTGA GGGTTGATTCCTAGTAAGAAACAGAATATGGGTCA GCCTTATG G AATTTGTC 1527 GACAAATT C CATAAGGC 1528 Adenomatous polyposis TAAAGCTGATATATGTGCTGTAGATGGTGCACTTGCATTTTTG 1529 coli GTTGGCACTCTTACTTAI C CGGAGCCAGACAAACACTTTAGCC Tyr622Term ATTATTGAAAGTGGAGGTGGGATATTACGGAATGTG TAC-TAA CACATTCCGTAATATCCCACCTCCACTTTCAATAATGGCTAAA 1530 GTGTTTGTCTGGCTCCG G TAAGTAAGAGTGCCAACCAAAAAT GCAAGTGCACCATCTACAGCACATATATCAGCTTTA CTTACTTA C CGGAGCCA 1531 TGGCTCCG G TAAGTAAG 1532 Adenomatous polyposis GATATATGTGCTGTAGATGGTGCACTTGCATTTTTGGTTGGCA 1533 coli CTCTTACTTACCGGAGC C AGACAAACACTTTAGCCATTATTGA Gln625Term AAGTGGAGGTGGGATATTACGGAATGTGTCCAGCT CAG-TAG AGCTGGACACATTCCGTAATATCCCACCTCCACTTTCAATAAT 1534 GGCTAAAGTGTTTGTCT G GCTCCGGTAAGTAAGAGTGCCAAC CAAAAATGCAAGTGCACCATCTACAGCACATATATC ACCGGAGC C AGACAAAC 1535 GTTTGTCT G GCTCCGGT 1536 Adenomatous polyposis TAGATGGTGCACTTGCATTTTTGGTTGGCACTCTTACTTACCG 1537 coli GAGCCAGACAAACACTT T AGCCATTATTGAAAGTGGAGGTGG Leu629Term GATATTACGGAATGTGTCCAGCTTGATAGCTACAAA TTA-TAA TTTGTAGCTATCAAGCTGGACACATTCCGTAATATCCCACCTC 1538 CACTTTCAATAATGGCT A AAGTGTTTGTCTGGCTCCGGTAAGT AAGAGTGCCAACCAAAAATGCAAGTGCACCATCTA AAACACTT T AGCCATTA 1539 TAATGGCT A AAGTGTTT 1540 Adenomatous polyposis GCCATTATTGAAAGTGGAGGTGGGATATTACGGAATGTGTCC 1541 coli AGCTTGATAGCTACAAAT G AGGACCACAGGTATATATAGAGTT Glu650Term TTATATTACTTTTAAAGTACAGAATTCATACTCTCA GAG-TAG TGAGAGTATGAATTCTGTACTTTAAAAGTAATATAAAACTCTAT 1542 ATATACCTGTGGTCCT C ATTTGTAGCTATCAAGCTGGACACAT TCCGTAATATCCCACCTCCACTTTCAATAATGGC CTACAAAT G AGGACCAC 1543 GTGGTCCT C ATTTGTAG 1544 Adenomatous polyposis TGCATGTGGAACTTTGTGGAATCTCTCAGCAAGAAATCCTAAA 1545 coli GACCAGGAAGCATTATG G GACATGGGGGCAGTTAGCATGCTC Trp699Term AAGAACCTCATTCATTCAAAGCACAAAATGATTGCT TGG-TGA AGCAATCATTTTGTGCTTTGAATGAATGAGGTTCTTGAGCATG 1546 CTAACTGCCCCCATGTC C CATAATGCTTCCTGGTCTTTAGGAT TTCTTGCTGAGAGATTCCACAAAGTTCCACATGCA GCATTATG G GACATGGG 1547 CCCATGTC C CATAATGC 1548 Adenomatous polyposis AAGACCAGGAAGCATTATGGGACATGGGGGCAGTTAGCATGC 1549 coli TCAAGAACCTCATTCATT C AAAGCACAAAATGATTGCTATGGG Ser713Term AAGTGCTGCAGCTTTAAGGAATCTCATGGCAAATAG TCA-TGA CTATTTGCCATGAGATTCCTTAAAGCTGCAGCACTTCCCATAG 1550 CAATCATTTTGTGCTTT G AATGAATGAGGTTCTTGAGCATGCT AACTGCCCCCCATGTCCCATAATGCTTCCTGGTCTT CATTCATT C AAAGCACA 1551 TGTGCTTT G AATGAATG 1552 Adenomatous polyposis GGGGCAGTTAGCATGCTCAAGAACCTCATTCATTCAAAGCAC 1553 coli AAAATGATTGCTATGGGA A GTGCTGCAGCTTTAAGGAATCTCA Ser722Gly TGGCAAATAGGCCTGCGAAGTACAAGGATGCCAATA AGT-GGT TATTGGCATCCTTGTACTTCGCAGGCCTATTTGCCATGAGATT 1554 CCTTAAAGCTGCAGCAC T TCCCATAGCAATCATTTTGTGCTTT GAATGAATGAGGTTCTTGAGCATGCTAACTGCCCC CTATGGGA A GTGCTGCA 1555 TGCAGCAC T TCCCATAG 1556 Adenomatous polyposis TCTCCTGGCTCAGCTTGCCATCTCTTCATGTTAGGAAACAAAA 1557 coli AGCCCTAGAAGCAGAAT T AGATGCTCAGCACTTATCAGAAACT Leu764Term TTTGACAATATAGACAATTTAAGTCCCAAGGCATC TTA-TAA GATGCCTTGGGACTTAAATTGTCTATATTGTCAAAAGTTTCTGA 1558 TAAGTGCTGAGCATCT A ATTCTGCTTCTAGGGCTTTTTGTTTC CTAACATGAAGAGATGGCAAGCTGAGCCAGGAGA AGCAGAAT T AGATGCTC 1559 GAGCATCT A ATTCTGCT 1560 Adenomatous polyposis TTAGATGCTCAGCACTTATCAGAAACTTTTGACAATATAGACAA 1561 coli TTTAAGTCCCAAGGCA T CTCATCGTAGTAAGCAGAGACACAG Ser784Thr CAAGTCTCTATGGTGATTATGTTTTTGACACCATC TCT-ACT GATGGTGTCAAAAACATAATCACCATAGAGACTTGCTGTGTCT 1562 CTGCTTACTACGATGAG A TGCCTTGGGACTTAAATTGTCTATA TTGTCAAAAGTTTCTGATAAGTGCTGAGCATCTAA CCAAGGCA T CTCATCGT 1563 ACGATGAG A TGCCTTGG 1564 Adenomatous potyposis CTCATCGTAGTAAGCAGAGACACAGCAAGTCTCTATGGTGATT 1565 coli ATGTTTTTGACACCAAT C GACATGATGATAATAGGTCAGACAT Arg805Term TTTAATACTGGCACATGACTGTCCTTTCACCATAT CGA-TGA ATATGGTGAAAGGACAGTCATGTGCCAGTATTAAAATGTCTGA 1566 CCTATTATCATCATGTC G ATTGGTGTCAAAAACATAATCACCAT AGAGACTTGCTGTGTCTCTGCTTACTACGATGAG ACACCAAT C GACATGAT 1567 ATCATGTC G ATTGGTGT 1568 Adenomatous polyposis GGTCTAGGCAACTACCATCCAGCAACAGAAAATCCAGGAACT 1569 coli TCTTCAAAGCGAGGTTTG C AGATCTCCACCACTGCAGCCCAG Gln879Term ATTGCCAAAGTCATGGAAGAAGTGTCAGCCATTCATA CAG-TAG TATGAATGGCTGACACTTCTTCCATGACTTTGGCAATCTGGGC 1570 TGCAGTGGTGGAGATCT G CAAACCTCGCTTTGAAGAAGTTCC TGGATTTTCTGTTGCTGGATGGTAGTTGCCTAGACC GAGGTTTG C AGATCTCC 1571 GGAGATCT G CAAACCTC 1572 Adenomatous polyposis TACATTGTGTGACAGATGAGAGAAATGCACTTAGAAGAAGCTC 1573 coli TGCTGCCCATACACATT C AAACACTTACAATTTCACTAAGTCG Ser932Term GAAAATTCAAATAGGACATGTTCTATGCCTTATGC TCA-TAA GCATAAGGCATAGAACATGTCCTATTTGAATTTTCCGACTTAG 1514 TGAAATTGTAAGTGTTT G AATGTGTATGGGCAGCAGAGCTTCT TCTAAGTGCATTTCTCTCATCTGTCACACAATGTA TACACATT C AAACACTT 1575 AAGTGTTT G AATGTGTA 1576 Adenomatous potyposis TACATTGTGTGACAGATGAGAGAAATGCACTTAGAAGAAGCTC 1577 coli TGCTGCCCATACACATT C AAACACTTACAATTTCACTAAGTCG Ser932Term GAAAATTCAAATAGGACATGTTCTATGCCTTATGC TCA-TGA GCATAAGGCATAGAACATGTCCTATTTGAATTTTCCGACTTAG 1578 TGAAATTGTAAGTGTTT G AATGTGTATGGGCAGCAGAGCTTCT TCTAAGTGCATTTCTCTCATCTGTCACACAATGTA TACACATT C AAACACTT 1579 AAGTGTTT G AATGTGTA 1580 Adenomatous polyposis GACAGATGAGAGAAATGCACTTAGAAGAAGCTCTGCTGCCCA 1581 coli TACACATTCAAACACTTA C AATTTCACTAAGTCGGAAAATTCAA Tyr935Term ATAGGACATGTTCTATGCCTTATGCCAAATTAGAA TAC-TAG TTCTAATTTGGCATAAGGCATAGAACATGTCCTATTTGAATTTT 1582 CCGACTTAGTGAAATT G TAAGTGTTTGAATGTGTATGGGCAGC AGAGCTTCTTCTAAGTGCATTTCTCTCATCTGTC AACACTTA C AATTTCAC 1583 GTGAAATT G TAAGTGTT 1584 Adenomatous polyposis GACAGATGAGAGAAATGCACTTAGAAGAAGCTCTGCTGCCCA 1585 coli TACACATTCAAACACTTA C AATTTCACTAAGTCGGAAAATTCAA Tyr935Term ATAGGACATGTTCTATGCCTTATGCCAAATTAGAA TAC-TAA TTCTAATTTGGCATAAGGCATAGAACATGTCCTATTTGAATTTT 1586 CCGACTTAGTGAAATT G TAAGTGTTTGAATGTGTATGGGCAGC AGAGCTTCTTCTAAGTGCATTTCTCTCATCTGTC AACACTTA C AATTTCAC 1587 GTGAAATT G TAAGTGTT 1588 Adenomatous polyposis ACCCTCGATTGAATCCTATTCTGAAGATGATGAAAGTAAGTTTT 1589 coli GCAGTTATGGTCAATA C CCAGCCGACCTAGCCCATAAAATACA Tyr1000Term TAGTGCAAATCATATGGATGATAATGATGGAGAA TAC-TAA TTCTCCATCATTATCATCCATATGATTTGCACTATGTATTTTAT 1590 GGGCTAGGTCGGCTGG G TATTGACCATAACTGCAAAACTTAC TTTCATCATCTTCAGAATAGGATTCAATCGAGGGT GGTCAATA C CCAGCCGA 1591 TCGGCTGG G TATTGACC 1592 Adenomatous polyposis TACCCAGCCGACCTAGCCCATAAAATACATAGTGCAAATCATA 1593 coli TGGATGATAATGATGGA G AACTAGATACACCAATAAATTATAG Glu1020Term TCTTAAATATTCAGATGAGCAGTTGAACTCTGGAA GAA-TAA TTCCAGAGTTCAACTGCTCATCTGAATATTTAAGACTATAATTT 1594 ATTGGTGTATCTAGTT C TCCATCATTATCATCCATATGATTTGC- ACTATGTATTTTATGGGCTAGGTCGGCTGGGTA ATGATGGA G AACTAGAT 1595 ATCTAGTT C TCCATCAT 1596 Adenomatous polyposis ATGAAACCCTCGATTGAATCCTATTCTGAAGATGATGAAAGTA 1597 coli AGTTTTGCAGTTATGGT C AATACCCAGCCGACCTAGCCCATAA Ser1032Term AATACATAGTGCAAATCATATGGATGATAATGATG TCA-TAA CATCATTATCATCCATATGATTTGCACTATGTATTTTATGGGCT 1598 AGGTCGGCTGGGTATT G ACCATAACTGCAAAACTTACTTTCAT CATCTTCAGAATAGGATTCAATCGAGGGTTTCAT GTTATGGT C AATACCCA 1599 TGGGTATT G ACCATAAC 1600 Adenomatous polyposis TGAAGATGATGAAAGTAAGTTTTGCAGTTATGGTCAATACCCA 1601 coli GCCGACCTAGCCCATAA A ATACATAGTGCAAATCATATGGATG Gln1041Term ATAATGATGGAGAACTAGATACACCAATAAATTAT CAA-TAA ATAATTTATTGGTGTATCTAGTTCTCCATCATTATCATCCATAT 1602 GATTTGCACTATGTAT T TTATGGGCTAGGTCGGCTGGGTATTG ACCATAACTGCAAAACTTACTTTCATCATCTTCA GCCCATAA A ATACATAG 1603 CTATGTAT T TTATGGGC 1604 Adenomatous polyposis ATAAATTATAGTCTTAAATATTCAGATGAGCAGTTGAACTCTGG 1605 coli AAGGCAAAGTCCTTCA C AGAATGAAAGATGGGCAAGACCCAA Gln1045Term ACACATAATAGAAGATGAAATAAAACAAAGTGAGC CAG-TAG GCTCACTTTGTTTTATTTCATCTTCTATTATGTGTTTGGGTCTT 1606 GCCCATCTTTCATTCT G TGAAGGACTTTGCCTTCCAGAGTTCA ACTGCTCATCTGAATATTTAAGACTATAATTTAT GTCCTTCA C AGAATGAA 1607 TTCATTCT G TGAAGGAC 1608 Adenomatous polyposis GAAAGATGGGCAAGACCCAAACACATAATAGAAGATGAAATAA 1609 coli AACAAAGTGAGCAAAGA C AATCAAGGAATCAAAGTACAACTTA Gln1067Term TCCTGTTTATACTGAGAGCACTGATGATAAACACC CAA-TAA GGTGTTTATCATCAGTGCTCTCAGTATAAACAGGATAAGTTGT 1610 ACTTTGATTCCTTGATT G TCTTTGCTCACTTTGTTTTATTTCATC TTCTATTATGTGTTTGGGTCTTGCCCATCTTTC AGCAAAGA C AATCAAGG 1611 CCTTGATT G TCTTTGCT 1612 Adenomatous polyposis AATAGAAGATGAAATAAAACAAAGTGAGCAAAGACAATCAAGG 1613 coli AATCAAAGTACAACTTA T CCTGTTTATACTGAGAGCACTGATG Tyr1075Term ATAAACACCTCAAGTTCCAACCACATTTTGGACAG TAT-TAG CTGTCCAAAATGTGGTTGGAACTTGAGGTGTTTATCATCAGTG 1614 CTCTCAGTATAAACAGG A TAAGTTGTACTTTGATTCCTTGATTG TCTTTGCTCACTTTGTTTTATTTCATCTTCTATT ACAACTTA T CCTGTTTA 1615 TAAACAGG A TAAGTTGT 1616 Adenomatous polyposis TGATGATAAACACCTCAAGTTCCAACCACATTTTGGACAGCAG 1617 coli GAATGTGTTTCTCCATA C AGGTCACGGGGAGCCAATGGTTCA Tyr1102Term GAAACAAATCGAGTGGGTTCTAATCATGGAATTAAT TAC-TAG ATTAATTCCATGATTAGAACCCACTCGATTTGTTTCTGAACCAT 1618 TGGCTCCCCGTGACCT G TATGGAGAAACACATTCCTGCTGTC CAAAATGTGGTTGGAACTTGAGGTGTTTATCATCA TCTCCATA C AGGTCACG 1619 CGTGACCT G TATGGAGA 1620 Adenomatous polyposis AACCACATTTTGGACAGCAGGAATGTGTTTCTCCATACAGGTC 1621 coli ACGGGGAGCCAATGGTT C AGAAACAAATCGAGTGGGTTCTAA Ser1110Term TCATGGAATTAATCAAAATGTAAGCCAGTCTTTGTG TCA-TGA CACAAAGACTGGCTTACATTTTGATTAATTCCATGATTAGAACC 1622 CACTCGATTTGTTTCT G AACCATTGGCTCCCCGTGACCTGTAT GGAGAAACACATTCCTGCTGTCCAAAATGTGGTT CAATGGTT C AGAAACAA 1623 TTGTTTCT G AACCATTG 1624 Adenomatous polyposis GGACAGCAGGAATGTGTTTCTCCATACAGGTCACGGGGAGCC 1625 coli AATGGTTCAGAAACAAAT C GAGTGGGTTCTAATCATGGAATTA Arg1114Term ATCAAAATGTAAGCCAGTCTTTGTGTCAAGAAGATG CGA-TGA CATCTTCTTGACACAAAGACTGGCTTACATTTTGATTAATTCCA 1626 TGATTAGAACCCACTC G ATTTGTTTCTGAACCATTGGCTCCCC GTGACCTGTATGGAGAAACACATTCCTGCTGTCC AAACAAAT C GAGTGGGT 1627 ACCCACTC G ATTTGTTT 1628 Adenomatous polyposis GGGTTCTAATCATGGAATTAATCAAAATGTAAGCCAGTCTTTG 1629 coli TGTCAAGAAGATGACTA T GAAGATGATAAGCCTACCAATTATA Tyr1135Term GTGAACGTTACTCTGAAGAAGAACAGCATGAAGAA TAT-TAG TTCTTCATGCTGTTCTTCTTCAGAGTAACGTTCACTATAATTGG 1630 TAGGCTTATCATCTTC A TAGTCATCTTCTTGACACAAAGACTG GCTTACATTTTGATTAATTCCATGATTAGAACCC GATGACTA T GAAGATGA 1631 TCATCTTC A TAGTCATC 1632 Adenomatous polyposis GAAGATGACTATGAAGATGATAAGCCTACCAATTATAGTGAAC 1633 coli GTTACTCTGAAGAAGAA C AGCATGAAGAAGAAGAGAGACCAA Gln1152Term CAAATTATAGCATAAAATATAATGAAGAGAAACGTC CAG-TAG GACGTTTCTCTTCATTATATTTTATGCTATAATTTGTTGGTCTCT 1634 CTTCTTCTTCATGCT G TTCTTCTTCAGAGTAACGTTCACTATAA TTGGTAGGCTTATCATCTTCATAGTCATCTTC AAGAAGAA C AGCATGAA 1635 TTCATGCT G TTCTTCTT 1636 Adenomatous polyposis GAAGAAGAGAGACCAACAAATTATAGCATAAAATATAATGAAG 1637 coli AGAAACGTCATGTGGAT C AGCCTATTGATTATAGTTTAAAATAT Gln1175Term GCCACAGATATTCCTTCATCACAGAAACAGTCAT CAG-TAG ATGACTGTTTCTGTGATGAAGGAATATCTGTGGCATATTTTAAA 1638 CTATAATCAATAGGCT G ATCCACATGACGTTTCTCTTCATTATA TTTTATGCTATAATTTGTTGGTCTCTCTTCTTC ATGTGGAT C AGCCTATT 1639 AATAGGCT G ATCCACAT 1640 Adenomatous polyposis AAGAGAGACCAACAAATTATAGCATAAAATATAATGAAGAGAA 1641 coli ACGTCATGTGGATCAGC C TATTGATTATAGTTTAAAATATGCCA Pro1176Leu CAGATATTCCTTCATCACAGAAACAGTCATTTTC CCT-CTT GAAAATGACTGTTTCTGTGATGAAGGAATATCTGTGGCATATT 1642 TTAAACTATAATCAATA G GCTGATCCACATGACGTTTCTCTTCA TTATATTTTATGCTATAATTTGTTGGTCTCTCTT GGATCAGC C TATTGATT 1643 AATCAATA G GCTGATCC 1644 Adenomatous polyposis ATAAAATATAATGAAGAGAAACGTCATGTGGATCAGCCTATTG 1645 coli ATTATAGTTTAAAATAT G CCACAGATATTCCTTCATCACAGAAA Ala1184Pro CAGTCATTTTCATTCTCAAAGAGTTCATCTGGAC GCC-CCC GTCCAGATGAACTCTTTGAGAATGAAAATGACTGTTTCTGTGA 1646 TGAAGGAATATCTGTGG C ATATTTTAAACTATAATCAATAGGCT GATCCACATGACGTTTCTCTTCATTATATTTTAT TAAAATAT G CCACAGAT 1647 ATCTGTGG C ATATTTTA 1648 Adenomatous polyposis ATCAGCCTATTGATTATAGTTTAAAATATGCCACAGATATTCCT 1649 coli TCATCACAGAAACAGT C ATTTTCATTCTCAAAGAGTTCATCTG Ser1194Term GACAAAGCAGTAAAACCGAACATATGTCTTCAAG TCA-TGA CTTGAAGACATATGTTCGGTTTTACTGCTTTGTCCAGATGAAC 1650 TCTTTGAGAATGAAAAT G ACTGTTTCTGTGATGAAGGAATATCT GTGGCATATTTTAAACTATAATCAATAGGCTGAT GAAACAGT C ATTTTCAT 1651 ATGAAAAT G ACTGTTTC 1652 Adenomatous polyposis ATTATAGTTTAAAATATGCCACAGATATTCCTTCATCACAGAAA 1653 coli CAGTCATTTTCATTCT C AAAGAGTTCATCTGGACAAAGCAGTA Ser1198Term AAACCGAACATATGTCTTCAAGCAGTGAGAATAC TCA-TGA GTATTCTCACTGCTTGAAGACATATGTTCGGTTTTACTGCTTTG 1654 TCCAGATGAACTCTTT G AGAATGAAAATGACTGTTTCTGTGAT GAAGGAATATCTGTGGCATATTTTAAACTATAAT TTCATTCT C AAAGAGTT 1655 AACTCTTT G AGAATGAA 1656 Adenomatous polyposis ACCGAACATATGTCTTCAAGCAGTGAGAATACGTCCACACCTT 1657 coli CATCTAATGCCAAGAGG C AGAATCAGCTCCATCCAGTTCTGC Gln1228Term ACAGAGTAGAAGTGGTCAGCCTCAAAGGCTGCCACT CAG-TAG AGTGGCAGCCTTTGAGGCTGACCACTTCTACTCTGTGCAGAA 1658 CTGGATGGAGCTGATTCT G CCTCTTGGCATTAGATGAAGGTG TGGACGTATTCTCACTGCTTGAAGACATATGTTCGGT CCAAGAGG C AGAATCAG 1659 CTGATTCT G CCTCTTGG 1660 Adenomatous polyposis CATATGTCTTCAAGCAGTGAGAATACGTCCACACCTTCATCTA 1661 coli ATGCCAAGAGGCAGAAT C AGCTCCATCCAGTTCTGCACAGAG Gln1230Term TAGAAGTGGTCAGCCTCAAAGGCTGCCACTTGCAAG CAG-TAG CTTGCAAGTGGCAGCCTTTGAGGCTGACCACTTCTACTCTGT 1662 GCAGAACTGGATGGAGCT G ATTCTGCCTCTTGGCATTAGATG AAGGTGTGGACGTATTCTCACTGCTTGAAGACATATG GGCAGAAT C AGCTCCAT 1663 ATGGAGCT G ATTCTGCC 1664 Adenomatous polyposis TCAGCTCCATCCAAGTTCTGCACAGAGTAGAAGTGGTCAGCC 1665 coli TCAAAAGGCTGCCACTTG C AAAGTTTCTTCTATTAACCAAGAA Cys1249Term ACAATACAGACTTATTGTGTAGAAGATACTCCAATA TGC-TGA TATTGGAGTATCTTCTACACAATAAGTCTGTATTGTTTCTTGGT 1666 TAATAGAAGAAACTTT G CAAGTGGCAGCCTTTTGAGGCTGACC ACTTCTACTCTGTGCAGAACTTGGATGGAGCTGA GCCACTTG C AAAGTTTC 1667 GAAACTTT G CAAGTGGC 1668 Adenomatous polyposis AGTTTCTTCTATTAACCAAGAAACAATACAGACTTATTGTGTAG 1669 coli AAGATACTCCAATATG T TTTTCAAGATGTAGTTCATTATCATCT Cys1270Term TTGTCATCAGCTGAAGATGAAATAGGATGTAAT TGT-TGA ATTACATCCTATTTCATCTTCAGCTGATGACAAAGATGATAATG 1670 AACTACATCTTGAAAA A CATATTGGAGTATCTTCTACACAATAA GTCTGTATTGTTTCTTGGTTAATAGAAGAAACT CCAATATG T TTTTCAAG 1671 CTTGAAAA A CATATTGG 1672 Adenomatous polyposis AAGAAACAATACAGACTTATTGTGTAGAAGATACTCCAATATGT 1673 coli TTTTCAAGATGTAGTT C ATTATCATCTTTGTCATCAGCTGAAGA Ser1276Term TGAAATAGGATGTAATCAGACGACACAGGAAGC TCA-TGA GCTTCCTGTGTCGTCTGATTACATCCTATTTCATCTTCAGCTG 1674 ATGACAAAGATGATAAT G AACTACATCTTGAAAAACATATTGGA GTATCTTCTACACAATAAGTCTGTATTGTTTCTT ATGTAGTT C ATTATCAT 1675 ATGATAAT G AACTACAT 1676 Adenomatous polyposis GATACTCCAATATGTTTTTCAAGATGTAGTTCATTATCATCTTT 1677 coli GTCATCAGCTGAAGAT G AAATAGGATGTAATCAGACGACACA Glu1286Term GGAAGCAGATTCTGCTAATACCCTGCAAATAGCAG GAA-TAA CTGCTATTTGCAGGGTATTAGCAGAATCTGCTTCCTGTGTCGT 1678 CTGATTACATCCTATTT C ATCTTCAGCTGATGACAAAGATGATA ATGAACTACATCTTGAAAAACATATTGGAGTATC CTGAAGAT G AAATAGGA 1679 TCCTATTT C ATCTTCAG 1680 Adenomatous polyposis TGTAGTTCATTATCATCTTTGTCATCAGCTGAAGATGAAATAGG 1681 coli ATGTAATCAGACGACA C AGGAAGCAGATTCTGCTAATACCCTG Gln1294Term CAAATAGCAGAAATAAAAGAAAAGATTGGAACTA CAG-TAG TAGTTCCAATCTTTTCTTTTATTTCTGCTATTTGCAGGGTATTA 1682 GCAGAATCTGCTTCCT G TGTCGTCTGATTACATCCTATTTCAT CTTCAGCTGATGACAAAGATGATAATGAACTACA AGACGACA C AGGAAGCA 1683 TGCTTCCT G TGTCGTCT 1684 Predisposition to, TAGGATGTAATCAGACGACACAGGAAGCAGATTCTGCTAATAC 1685 association with, CCTGCAAATAGCAGAAA T AAAAGAAAAGATTGGAACTAGGTCA colorectal cancer GCTGAAGATCCTGTGAGCGAAGTTCCAGCAGTGTC Ile1307Lys ATA-AAA GACACTGCTGGAACTTCGCTCACAGGATCTTCAGCTGACCTA 1686 GTTCCAATCTTTTCTTTT A TTTCTGCTATTTGCAGGGTATTAGC AGAATCTGCTTCCTGTGTCGTCTGATTACATCCTA AGCAGAAA T AAAAGAAA 1687 TTTCTTTT A TTTCTGCT 1688 Adenomatous polyposis CCAAGAAACAATACAGACTTATTGTGTAGAAGATACTCCAATA 1689 coil TGTTTTTCAAGATGTAG T TCATTATCATCTTTGTCATCAGCTGA Glu1309Term AGATGAAATAGGATGTAATCAGACGACACAGGAA GAA-TAA TTCCTGTGTCGTCTGATTACATCCTATTTCATCTTCAGCTGATG 1690 ACAAAGATGATAATGA A CTACATCTTGAAAAACATATTGGAGTA TCTTCTACACAATAAGTCTGTATTGTTTCTTGG AGATGTAG T TCATTATC 1691 GATAATGA A CTACATCT 1692 Predisposition to GATTCTGCTAATACCCTGCAAATAGCAGAAATAAAAGAAAAGA 1693 Colorectal Cancer TTGGAACTAGGTCAGCT G AAGATCCTGTGAGCGAAGTTCCAG Glu1317Gln CAGTGTCACAGCACCCTAGAACCAAATCCAGCAGAC GAA-CAA GTCTGCTGGATTTGGTTCTAGGGTGCTGTGACACTGCTGGAA 1694 CTTCGCTCACAGGATCTT C AGCTGACCTAGTTCCAATCTTTTC TTTTATTTCTGCTATTTGCAGGGTATTAGCAGAATC GGTCAGCT G AAGATCCT 1695 AGGATCTT C AGCTGACC 1696 Adenomatous polyposis AAAGAAAAGATTGGAACTAGGTCAGCTGAAGATCCTGTGAGC 1697 coli GAAGTTCCAGCAGTGTCA C AGCACCCTAGAACCAAATCCAGC Gln1328Term AGACTGCAGGGTTCTAGTTTATCTTCAGAATCAGCCA CAG-TAG TGGCTGATTCTGAAGATAAACTAGAACCCTGCAGTCTGCTGG 1698 ATTTGGTTCTAGGGTGCT G TGACACTGCTGGAACTTCGCTCA CAGGATCTTCAGCTGACCTAGTTCCAATCTTTTCTTT CAGTGTCA C AGCACCCT 1699 AGGGTGCT G TGACACTG 1700 Adenomatous polyposis GATCCTGTGAGCGAAGTTCCAGCAGTGTCACAGCACCCTAGA 1701 coli ACCAAATCCAGCAGACTG C AGGGTTCTAGTTTATCTTCAGAAT Gln1338Term CAGCCAGGCACAAAGCTGTTGAATTTTCTTCAGGAG CAG-TAG CTCCTGAAGAAAATTCAACAGCTTTGTGCCTGGCTGATTCTGA 1702 AGATAAACTAGAACCCT G CAGTCTGCTGGATTTGGTTCTAGG GTGCTGTGACACTGCTGGAACTTCGCTCACAGGATC GCAGACTG C AGGGTTCT 1703 AGAACCCT G CAGTCTGC 1704 Adenomatous polyposis AAGTTCCAGCAGTGTCACAGCACCCTAGAACCAAATCCAGCA 1705 coli GACTGCAGGGTTCTAGTT T ATCTTCAGAATCAGCCAGGCACAA Leu1342Term AGCTGTTGAATTTTCTTCAGGAGCGAAATCTCCCTC TTA-TAA GAGGGAGATTTCGCTCCTGAAGAAAATTCAACAGCTTTGTGC 1706 CTGGCTGATTCTGAAGAT A AACTAGAACCCTGCAGTCTGCTG GATTTGGTTCTAGGGTGCTGTGACACTGCTGGAACTT TTCTAGTT T ATCTTCAG 1707 CTGAAGAT A AACTAGAA 1708 Adenomatous polyposis CAGCACCCTAGAACCAAATCCAGCAGACTGCAGGGTTCTAGT 1709 coli TTATCTTCAGAATCAGCC A GGCACAAAGCTGTTGAATTTTCTT Arg1348Trp CAGGAGCGAAATCTCCCTCCCGAAAGTGGTGCTCAG AGG-TGG CTGAGCACCACTTTCGGGAGGGAGATTTCGCTCCTGAAGAAA 1710 ATTCAACAGCTTTGTGCC T GGCTGATTCTGAAGATAAACTAGA ACCCTGCAGTCTGCTGGATTTGGTTCTAGGGTGCTG AATCAGCC A GGCACAAA 1711 TTTGTGCC T GGCTGATT 1712 Adenomatous polyposis CTGCAGGGTTCTAGTTTATCTTCAGAATCAGCCAGGCACAAAG 1713 coli CTGTTGAATTTTCTTCA G GAGCGAAATCTCCCTCCCGAAAGTG Gly1357Term GTGCTCAGACACCCCAAAGTCCACCTGAACACTAT GGA-TGA ATAGTGTTCAGGTGGACTTTGGGGTGTCTGAGCACCACTTTC 1714 GGGAGGGAGATTTCGCTC C TGAAGAAAATTCAACAGCTTTGT GCCTGGCTGATTCTGAAGATAAACTAGAACCCTGCAG TTTCTTCA G GAGCGAAA 1715 TTTCGCTC C TGAAGAAA 1716 Adenomatous polyposis CCAGGCACAAAGCTGTTGAATTTTCTTCAGGAGCGAAATCTCC 1717 coli CTCCCGAAAGTGGTGCT C AGACACCCCAAAGTCCACCTGAAC Gln1367Term ACTATGTTCAGGAGACCCCACTCATGTTTAGCAGAT CAG-TAG ATCTGCTAAACATGAGTGGGGTCTCCTGAACATAGTGTTCAG 1718 GTGGACTTTGGGGTGTCT G AGCACCACTTTCGGGAGGGAGAT TTCGCTCCTGAAGAAAATTCAACAGCTTTGTGCCTGG GTGGTGCT C AGACACCC 1719 GGGTGTCT G AGCACCAC 1720 Adenomatous polyposis AAAGCTGTTGAATTTTCTTCAGGAGCGAAATCTCCCTCCAAAA 1721 coli GTGGTGCTCAGACACCC A AAAGTCCACCTGAACACTATGTTC Lys1370Term AGGAGACCCCACTCATGTTTAGCAGATGTACTTCTG AAA-TAA CAGAAGTACATCTGCTAAACATGAGTGGGGTCTCCTGAACATA 1722 GTGTTCAGGTGGACTTT T GGGTGTCTGAGCACCACTTTTGGA GGGAGATTTCGCTCCTGAAGAAAATTCAACAGCTTT AGACACCC A AAAGTCCA 1723 TGGACTTT T GGGTGTCT 1724 Adenomatous polyposis CACCTGAACACTATGTTCAGGAGACCCCACTCATGTTTAGCA 1725 coli GATGTACTTCTGTCAGTT C ACTTGATAGTTTTGAGAGTCGTTC Ser1392Term GATTGCCAGCTCCGTTCAGAGTGAACCATGCAGTGG TCA-TAA CCACTGCATGGTTCACTCTGAACGGAGCTGGCAATCGAACGA 1726 CTCTCAAAACTATCAAGT G AACTGACAGAAGTACATCTGCTAA ACATGAGTGGGGTCTCCTGAACATAGTGTTCAGGTG TGTCAGTT C ACTTGATA 1727 TATCAAGT G AACTGACA 1728 Adenomatous polyposis CACCTGAACACTATGTTCAGGAGACCCCACTCATGTTTAGCA 1729 coli GATGTACTTCTGTCAGTT C ACTTGATAGTTTTGAGAGTCGTTC Ser1392Term GATTGCCAGCTCCGTTCAGAGTGAACCATGCAGTGG TCA-TGA CCACTGCATGGTTCACTCTGAACGGAGCTGGCAATCGAACGA 1730 CTCTCAAAACTATCAAGT G AACTGACAGAAGTACATCTGCTAA ACATGAGTGGGGTCTCCTGAACATAGTGTTCAGGTG TGTCAGTT C ACTTGATA 1731 TATCAAGT G AACTGACA 1732 Adenomatous polyposis GTTCAGGAGACCCCACTCATGTTTAGCAGATGTACTTCTGTCA 1733 coli GTTCACTTGATAGTTTT G AGAGTCGTTCGATTGCCAGCTCCGT Glu1397Term TCAGAGTGAACCATGCAGTGGAATGGTAGGTGGCA GAG-TAG TGCCACCTACCATTCCACTGCATGGTTCACTCTGAACGGAGC 1734 TGGAATCGAACGACTCT C AAAACTATCAAGTGAACTGACAGA AGTACATCTGCTAAACATGAGTGGGGTCTCCTGAAC ATAGTTTT G AGAGTCGT 1735 ACGACTCT C AAAACTAT 1736 Adenomatous polyposis CAAACCATGCCACCAAGCAGAAGTAAAACACCTCCACCACCT 1737 coli CCTCAAACAGCTCAAACC A AGCGAGAAGTACCTAAAAATAAAG Lys1449Term CACCTACTGCTGAAAAGAGAGAGAGTGGACCTAAGC AAG-TAG GCTTAGGTCCACTCTCTCTCTTTTCAGCAGTAGGTGCTTTATT 1738 TTTAGGTACTTCTCGCT T GGTTTGAGCTGTTTGAGGAGGTGGT GGAGGTGTTTTACTTCTGCTTGGTGGCATGGTTTG CTCAAACC A AGCGAGAA 1739 TTCTCGCT T GGTTTGAG 1740 Adenomatous polyposis ACCATGCCACCAAGCAGAAGTAAAACACCTCCACCACCTCCT 1741 coli CAAACAGCTCAAACCAAG C GAGAAGTACCTAAAAATAAAGCAC Arg1450Term CTACTGCTGAAAAGAGAGAGAGTGGACCTAAGCAAG CGA-TGA CTTGCTTAGGTCCACTCTCTCTCTTTTCAGCAGTAGGTGCTTT 1742 ATTTTTAGGTACTTCTC G CTTGGTTTGAGCTGTTTGAGGAGGT GGTGGAGGTGTTTTACTTCTGCTTGGTGGCATGGT AAACCAAG C GAGAAGTA 1743 TACTTCTC G CTTGGTTT 1744 Adenomatous polyposis CAGATGCTGATACTTTATTACATTTTGCCACGGAAAGTACTCC 1145 coli AGATGGATTTTCTTGTT C ATCCAGCCTGAGTGCTCTGAGCCTC SeR1503Term GATGAGCCATTTATACAGAAAGATGTGGAATTAAG TCA-TAA CTTAATTCCACATCTTTCTGTATAAATGGCTCATCGAGGCTCA 1746 GAGCACTCAGGCTGGAT G AACAAGAAAATCCATCTGGAGTAC TTTCCGTGGCAAAATGTAATAAAGTATCAGCATCTG TTCTTGTT C ATCCAGCC 1747 GGCTGGAT G AACAAGAA 1748 Adenomatous polyposis CTGAGCCTCGATGAGCCATTTATACAGAAAGATGTGGAATTAA 1749 coli GAATAATGCCTCCAGTT C AGGAAAATGACAATGGGAATGAAAC Gln1529Term AGAATCAGAGCAGCCTAAAGAATCAAATGAAAACC CAG-TAG GGTTTTCATTTGATTCTTTAGGCTGCTCTGATTCTGTTTCATTC 1750 CCATTGTCATTTTCCT G AACTGGAGGCATTATTCTTAATTCCAC ATCTTTCTGTATAAATGGCTCATCGAGGCTCAG CTCCAGTT C AGGAAAAT 1751 ATTTTCCT G AACTGGAG 1752 Adenomatous polyposis ATGTGGAATTAAGAATAATGCCTCCAGTTCAGGAAAATGACAA 1753 coli TGGGAATGAAACAGAAT C AGAGCAGCCTAAAGAATCAAATGAA Ser1539Term AACCAAGAGAAAGAGGCAGAAAAAACTATTGATTC TCA-TAA GAATCAATAGTTTTTTCTGCCTCTTTCTCTTGGTTTTCATTTGA 1754 TTCTTTAGGCTGCTCT G ATTCTGTTTCATTCCCATTGTCATTTT CCTGAACTGGAGGCATTATTCTTAATTCCACAT AACAGAAT C AGAGCAGC 1755 GCTGCTCT G ATTCTGTT 1756 Adenomatous polyposis AAAACCAAGAGAAAGAGGCAGAAAAAACTATTGATTCTGAAAA 1757 coli GGACCTATTAGATGATT C AGATGATGATGATATTGAAATACTA Ser1567Term GAAGAATGTATTATTTCTGCCATGCCAACAAAGTC TCA-TGA GACTTTGTTGGCATGGCAGAAATAATACATTCTTCTAGTATTTC 1758 AATATCATCATCATCT G AATCATCTAATAGGTCCTTTTCAGAAT CAATAGTTTTTTCTGCCTCTTTCTCTTGGTTTT AGATGATT C AGATGATG 1759 CATCATCT G AATCATCT 1760 Adenomatous poiyposis AGAGAGTTTTCTCAGACAACAAAGATTCAAAGAAACAGAATTT 1761 coli GAAAAATAATTCCAAGG A CTTCAATGATAAGCTCCCAAATAAT Asp1822Val GAAGATAGAGTCAGAGGAAGTTTTGCTTTTGATTC GAC-GTC GAATCAAAAGCAAAACTTCCTCTGACTCTATCTTCATTATTTGG 1762 GAGCTTATCATTGAAG T CCTTGGAATTATTTTTCAAATTCTGTT TCTTTGAATCTTTGTTGTCTGAGAAAACTCTCT TTCCAAGG A CTTCAATG 1763 CATTGAAG T CCTTGGAA 1764 Adenomatous polyposis AAAACTGACAGCACAGAATCCAGTGGAACCCAAAGTCCTAAG 1765 coli CGCCATTCTGGGTCTTAC C TTGTGACATCTGTTTAAAAGAGAG Leu2839Phe GAAGAATGAAACTAAGAAAATTCTATGTTAATTACA CTT-TTT TGTAATTAACATAGAATTTTCTTAGTTTCATTCTTCCTCTCTTTT 1766 AAACAGATGTCACAA G GTAAGACCCAGAATGGCGCTTAGGAC TTTGGGTTCCACTGGATTCTGTGCTGTCAGTTTT GGTCTTAC C TTGTGACA 1767 TGTCACAA G GTAAGACC 1768

EXAMPLE 12 Parahemophilia—Factor V Deficiency

Deficiency in clotting Factor V is associated with a lifelong predisposition to thrombosis. The disease typically manifests itself with usually mild bleeding, although bleeding times and clotting times are consistently prolonged. Individuals that are heterozygous for a mutation in Factor V have lowered levels of factor V but probably never have abnormal bleeding. A large number of alleles with a range of presenting symptoms have been identified. The attached table discloses the correcting oligonucleotide base sequences for the Factor V oligonucleotides of the invention.

TABLE 19 Factor V Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Factor V deficiency TTGACTGAATGCTTATTTTGGCCTGTGTCTCTCCCTCTTTCTCA 4340 Ala221Val GATATAACAGTTTGTG C CCATGACCACATCAGCTGGCATCTGC GCC-GTC TGGGAATGAGCTCGGGGCCAGAATTATTCTCCAT ATGGAGAATAATTCTGGCCCCGAGCTCATTCCCAGCAGATGC 1769 CAGCTGATGTGGTCATGG G CACAAACTGTTATATCTGAGAAAG AGGGAGAGACACAGGCCAAAATAAGCATTCAGTCAA AGTTTGTG C CCATGACC 1770 GGTCATGG G CACAAACT 1771 Thrombosis TGTCCTAACTCAGCTGGGATGCAGGCTTACATTGACATTAAAA 1712 Arg306Gly ACTGCCCAAAGAAAACC A GGAATCTTAAGAAAATAACTCGTGA AGG-GGG GCAGAGGCGGCACATGAAGAGGTGGGAATACTTCA TGAAGTATTCCCACCTCTTCATGTGCCGCCTCTGCTCACGAGT 1773 TATTTTCTTAAGATTCC T GGTTTTCTTTGGGCAGTTTTTAATGT CAATGTAAGCCTGCATCCCAGCTGAGTTAGGACA AGAAAACC A GGAATCTT 1774 AAGATTCC T GGTTTTCT 1775 Thrombosis GTCCTAACTCAGCTGGGATGCAGGCTTACATTGACATTAAAAA 1776 Arg306Thr CTGCCCAAAGAAAACCA G GAATCTTAAGAAAATAACTCGTGAG AGG-ACG CAGAGGCGGCACATGAAGAGGTGGGAATACTTCAT ATGAAGTATTCCCACCTCTTCATGTGCCGCCTCTGCTCACGA 1777 GTTATTTTCTTAAGATTC C TGGTTTTCTTTGGGCAGTTTTTAAT GTCAATGTAAGCCTGCATCCCAGCTGAGTTAGGAC GAAAACCA G GAATCTTA 1778 TAAGATTC C TGGTTTTC 1779 Increased Risk CCACAGAAAATGATGCCCAGTGCTTAACAAGACCATACTACAG 1780 Thrombosis TGACGTGGACATCATGA G AGACATCGCCTCTGGGCTAATAGG Arg485Lys ACTACTTCTAATCTGTAAGAGCAGATCCCTGGACAG AGA-AAA CTGTCCAGGGATCTGCTCTTACAGATTAGAAGTAGTCCTATTA 1781 GCCCAGAGGCGATGTCT C TCATGATGTCCACGTCACTGTAGT ATGGTCTTGTTAAGCACTGGGCATCATTTTCTGTGG CATCATGA G AGACATCG 1782 CGATGTCT C TCATGATG 1783 Increased Risk ACATCGCCTCTGGGCTAATAGGACTACTTCTAATCTGTAAGAG 1784 Thrombosis CAGATCCCTGGACAGGC G AGGAATACAGGTATTTTGTCCTTG Arg506Gln AAGTAACCTTTCAGAAATTCTGAGAATTTCTTCTGG CGA-CAA CCAGAAGAAATTCTCAGAATTTCTGAAAGGTTACTTCAAGGAC 1785 AAAATACCTGTATTCCT C GCCTGTCCAGGGATCTGCTCTTACA GATTAGAAGTAGTCCTATTAGCCCAGAGGCGATGT GGACAGGC G AGGAATAC 1786 GTATTCCT C GCCTGTCC 1787 Factor V Deficiency GACATCGCCTCTGGGCTAATAGGACTACTTCTAATCTGTAAGA 1788 Arg506Term GCAGATCCCTGGACAGG C GAGGAATACAGGTATTTTGTCCTT CGA-TGA GAAGTAACCTTTCAGAAATTCTGAGAATTTCTTCTG CAGAAGAAATTCTCAGAATTTCTGAAAGGTTACTTCAAGGACA 1789 AAATACCTGTATTCCTC G CCTGTCCAGGGATCTGCTCTTACAG ATTAGAAGTAGTCCTATTAGCCCAGAGGCGATGTC TGGACAGG C GAGGAATA 1790 TATTCCTC G CCTGTCCA 1791 Thrombosis AGTGATGCTGACTATGATTACCAGAACAGACTGGCTGCAGCA 1792 Arg712Term TTAGGAATCAGGTCATTC C GAAACTCATCATTGAATCAGGAAG CGA-TGA AAGAAGAGTTCAATCTTACTGCCCTAGCTCTGGAGA TCTCCAGAGCTAGGGCAGTAAGATTGAACTCTTCTTCTTCCTG 1793 ATTCAATGATGAGTTTC G GAATGACCTGATTCCTAATGCTGCA GCCAGTCTGTTCTGGTAATCATAGTCAGCATCACT GGTCATTC C GAAACTCA 1794 TGAGTTTC G GAATGACC 1795 Thrombosis TCAGTCAGACAAACCTTTCCCCAGCCCTCGGTCAGATGCCCA 1796 His1299Arg TTTCTCCAGACCTCAGCC A TACAACCCTTTCTCTAGACTTCAG CAT-CGT CCAGACAAACCTCTCTCCAGAACTCAGTCAAACAAA TTTGTTTGACTGAGTTCTGGAGAGAGGTTTGTCTGGCTGAAGT 1797 CTAGAGAAAGGGTTGTA T GGTCTGGAGAAATGGGCA TCTGACCGAGGGCTGGGGAAAGGTTTGTCTGACTGA CCTCAGCC A TACAACCC 1798 GGGTTGTA T GGCTGAGG 1799

EXAMPLE 13 Hemophilia—Factor VIII Deficiency

The attached table discloses the correcting oligonucleotide base sequences for the Factor VIII oligonucleotides of the invention.

TABLE 20 Factor VIII Mutations and Genome-Correcting Oligos ClinicaI Phenotype & SEQ ID Mutation Correcting Oligos NO: Haemophilia A AGCTCTCCACCTGCTTCTTTCTGTGCCTTTTGCGATTCTGCTT 1800 Tyr5Cys TAGTGCCACCAGAAGAT A CTACCTGGGTGCAGTGGAACTGTC TAC-TGC ATGGGACTATATGCAAAGTGATCTCGGTGAGCTGCC GGCAGCTCACCGAGATCACTTTGCATATAGTCCCATGACAGT 1801 TCCACTGCACCCAGGTAG T ATCTTCTGGTGGCACTAAAGCAG AATCGCAAAAGGCACAGAAAGAAGCAGGTGGAGAGCT CAGAAGAT A CTACCTGG 1802 CCAGGTAG T ATCTTCTG 1803 Haemophilia A CCACCTGCTTCTTTCTGTGCCTTTTGCGATTCTGCTTTAGTGC 1804 Leu7Arg CACCAGAAGATACTACC T GGGTGCAGTGGAACTGTCATGGGA CTG-CGG CTATATGCAAAGTGATCTCGGTGAGCTGCCTGTGGA TCCACAGGCAGCTCACCGAGATCACTTTGCATATAGTCCCAT 1805 GACAGTTCCACTGCACCC A GGTAGTATCTTCTGGTGGCACTA AAGCAGAATCGCAAAAGGCACAGAAAGAAGCAGGTGG ATACTACC T GGGTGCAG 1806 CTGCACCC A GGTAGTAT 1807 Haemophilia A AGTCATGCAAATAGAGCTCTCCACCTGCTTCTTTCTGTGCCTT 1808 Ser(−1)Arg TTGCGATTCTGCTTTAG T GCCACCAGAAGATACTACCTGGGT AGTg-AGG GCAGTGGAACTGTCATGGGACTATATGCAAAGTGAT ATCACTTTGCATATAGTCCCATGACAGTTCCACTGCACCCAG 1809 GTAGTATCTTCTGGTGGC A CTAAAGCAGAATCGCAAAAGGCA CAGAAAGAAGCAGGTGGAGAGCTCTATTTGCATGACT TGCTTTAG T GCCACCAG 1810 CTGGTGGC A CTAAAGCA 1811 Haemophilia A CATTTGTAGCAAATAAGTCATGCAAATAGAGCTCTCCACCTGCT 1812 Arg(−5)Term TCTTTCTGTGCCTTTTG C GATTCTGCTTTAGTGCCACCAGAAG gCGA-TGA ATACTACCTGGGTGCAGTGGAACTGTCATGGGACT AGTCCCATGACAGTTCCACTGCACCCAGGTAGTATCTTCTGG 1813 TGGCACTAAAGCAGAATC G CAAAAGGCACAGAAAGAAGCAGG TGGAGAGCTCTATTTGCATGACTTATTGCTACAAATG GCCTTTTG C GATTCTGC 1814 GCAGAATC G CAAAAGGC 1815 Haemophilia A TTCTGTGCCTTTTGCGATTCTGCTTTAGTGCCACCAGAAGATA 1816 Glu11Val CTACCTGGGTGCAGTGG A ACTGTCATGGGACTATATGCAAAG GAA-GTA TGATCTCGGTGAGCTGCCTGTGGACGCAAGGTAAAG CTTTACCTTGCGTCCACAGGCAGCTCACCGAGATCACTTTGC 1817 ATATAGTCCCATGACAGT T CCACTGCACCCAGGTAGTATCTTC TGGTGGCACTAAAGCAGAATCGCAAAAGGCACAGAA TGCAGTGG A ACTGTCAT 1818 ATGACAGT T CCACTGCA 1819 Haemophilia A CTTTTGCGATTCTGCTTTAGTGCCACCAGAAGATACTACCTGG 1820 Trp14Gly GTGCAGTGGAACTGTCA T GGGACTATATGCAAAGTGATCTCG aTGG-GGG GTGAGCTGCCTGTGGACGCAAGGTAAAGGCATGTCC GGACATGCCTTTACCTTGCGTCCACAGGCAGCTCACCGAGAT 1821 CACTTTGCATATAGTCCC A TGACAGTTCCACTGCACCCAGGT AGTATCTTCTGGTGGCACTAAAGCAGAATCGCAAAAG AACTGTCA T GGGACTAT 1822 ATAGTCCC A TGACAGTT 1823 Haemophilia A TTCACGCAGATTTCCTCCTAGAGTGCCAAAATCTTTTCCATTC 1824 Tyr46Term AACACCTCAGTCGTGTA C AAAAAGACTCTGTTTGTAGAATTCA TACa-TAA CGGATCACCTTTTCAACATCGCTAAGCCAAGGCCA TGGCCTTGGCTTAGCGATGTTGAAAAGGTGATCCGTGAATTC 1825 TACAAACAGAGTCTTTTTGTACACGACTGAGGTGTTGAATGGA AAAGATTTTGGCACTCTAGGAGGAAATCTGCGTGAA GTCGTGTA C AAAAAGAC 1826 GTCTTTTT G TACACGAC 1827 Haemophilia A ATCTTTTCCATTCAACACCTCAGTCGTGTACAAAAAGACTCTG 1828 Asp56Glu TTTGTAGAATTCACGGA T CACCTTTTCAACATCGCTAAGCCAA GATc-GAA GGCCACCCTGGATGGGTAATGAAAACAATGTTGAA TTCAACATTGTTTTCATTACCCATCCAGGGTGGCCTTGGCTTA 1829 GCGATGTTGAAAAGGTG A TCCGTGAATTCTACAAACAGAGTC TTTTTGTACACGACTGAGGTGTTGAATGGAAAAGAT TTCACGGA T CACCTTTT 1830 AAAAGGTG A TCCGTGAA 1831 Haemophilia A TTCTGGAGTACTATCCCCAAGTAACCTTTGGCGGACATCTCAT 1832 Gly73Val TCTTACAGGTCTGCTAG G TCCTACCATCCAGGCTGAGGTTTA GGT-GTT TGATACAGTGGTCATTACACTTAAGAACATGGCTTC GAAGCCATGTTCTTAAGTGTAATGACCACTGTATCATAAACCT 1833 CAGCCTGGATGGTAGGA C CTAGCAGACCTGTAAGAATGAGAT GTCCGCCAAAGGTTACTTGGGGATAGTACTCCAGAA TCTGCTAG G TCCTACCA 1834 TGGTAGGA C CTAGCAGA 1835 Haemophilia A CAAGTAACCTTTGGCGGACATCTCATTCTTACAGGTCTGCTAG 1836 Glu79Lys GTCCTACCATCCAGGCT G AGGTTTATGATACAGTGGTCATTAC tGAG-AAG ACTTAAGAACATGGCTTCCCATCCTGTCAGTCTTC GAAGACTGACAGGATGGGAAGCCATGTTCTTAAGTGTAATGA 1837 CCACTGTATCATAAACCT C AGCCTGGATGGTAGGACCTAGCA GACCTGTAAGAATGAGATGTCCGCCAAAGGTTACTTG TCCAGGCT G AGGTTTAT 1838 ATAAACCT C AGCCTGGA 1839 Haemophilia A TAACCTTTGGCGGACATCTCATTCTTACAGGTCTGCTAGGTCC 1840 Val80Asp TACCATCCAGGCTGAGG T TTATGATACAGTGGTCATTACACTT GTT-GAT AAGAACATGGCTTCCCATCCTGTCAGTCTTCATGC GCATGAAGACTGACAGGATGGGAAGCCATGTTCTTAAGTGTA 1841 ATGACCACTGTATCATAA A CCTCAGCCTGGATGGTAGGACCT AGCAGACCTGTAAGAATGAGATGTCCGCCAAAGGTTA GGCTGAGG T TTATGATA 1842 TATCATAA A CCTCAGCC 1843 Haemophilia A TTGGCGGACATCTCATTCTTACAGGTCTGCTAGGTCCTACCAT 1844 Asp82Val CCAGGCTGAGGTTTATG A TACAGTGGTCATTACACTTAAGAAC GAT-GTT ATGGCTTCCCATCCTGTCAGTCTTCATGCTGTTGG CCAACAGCATGAAGACTGACAGGATGGGAAGCCATGTTCTTA 1845 AGTGTAATGACCACTGTA T CATAAACCTCAGCCTGGATGGTA GGACCTAGCAGACCTGTAAGAATGAGATGTCCGCCAA GGTTTATG A TACAGTGG 1846 CCACTGTA T CATAAACC 1847 Haemophilia A TTGGCGGACATCTCATTCTTACAGGTCTGCTAGGTCCTACCAT 1848 Asp82Gly CCAGGCTGAGGTTTATG A TACAGTGGTCATTACACTTAAGAAC GAT-GGT ATGGCTTCCCATCCTGTCAGTCTTCATGCTGTTGG CCAACAGCATGAAGACTGACAGGATGGGAAGCCATGTTCTTA 1849 AGTGTAATGACCACTGTA T CATAAACCTCAGCCTGGATGGTA- GGACCTAGCAGACCTGTAAGAATGAGATGTCCGCCAA GGTTTATG A TACAGTGG 1850 CCACTGTA T CATAAACC 1851 Haemophilia A ATCTCATTCTTACAGGTCTGCTAGGTCCTACCATCCAGGCTGA 1852 Val85Asp GGTTTATGATACAGTGG T CATTACACTTAAGAACATGGCTTCC GTC-GAC CATCCTGTCAGTCTTCATGCTGTTGGTGTATCCTA TAGGATACACCAACAGCATGAAGACTGACAGGATGGGAAGCC 1853 ATGTTCTTAAGTGTAATG A CCACTGTATCATAAACCTCAGCCT GGATGGTAGGACCTAGCAGACCTGTAAGAATGAGAT TACAGTGG T CATTACAC 1854 GTGTAATG A CCACTGTA 1855 Haemophilia A CAGGTCTGCTAGGTCCTACCATCCAGGCTGAGGTTTATGATA 1856 Lys89Thr CAGTGGTCATTACACTTA A GAACATGGCTTCCCATCCTGTCA AAG-ACG GTCTTCATGCTGTTGGTGTATCCTACTGGAAAGCTTC GAAGCTTTCCAGTAGGATACACCAACAGCATGAAGACTGACA 1857 GGATGGGAAGCCATGTTC T TAAGTGTAATGACCACTGTATCAT AAACCTCAGCCTGGATGGTAGGACCTAGCAGACCTG TACACTTA A GAACATGG 1858 CCATGTTC T TAAGTGTA 1859 Haemophilia A CTGCTAGGTCCTACCATCCAGGCTGAGGTTTATGATACAGTG 1860 Met91Val GTCATTACACTTAAGAAC A TGGCTTCCCATCCTGTCAGTCTTC cATG-GTG ATGCTGTTGGTGTATCCTACTGGAAAGCTTCTGAGG CCTCAGAAGCTTTCCAGTAGGATACACCAACAGCATGAAGAC 1861 TGACAGGATGGGAAGCCA T GTTCTTAAGTGTAATGACCACTG TATCATAAACCTCAGCCTGGATGGTAGGACCTAGCAG TTAAGAAC A TGGCTTCC 1862 GGAAGCCA T GTTCTTAA 1863 Haemophilia A CTACCATCCAGGCTGAGGTTTATGATACAGTGGTCATTACACT 1864 His94Arg TAAGAACATGGCTTCCC A TCCTGTCAGTCTTCATGCTGTTGGT CAT-CGT GTATCCTACTGGAAAGCTTCTGAGGGTGAGTAAAA TTTTACTCACCCTCAGAAGCTTTCCAGTAGGATACACCAACAG 1865 CATGAAGACTGACAGGA T GGGAAGCCATGTTCTTAAGTGTAA TGACCACTGTATCATAAACCTCAGCCTGGATGGTAG GGCTTCCC A TCCTGTCA 1866 TGACAGGA T GGGAAGCC 1867 Haemophilia A CCTACCATCCAGGCTGAGGTTTATGATACAGTGGTCATTACAC 1868 His94Tyr TTAAGAACATGGCTTCC C ATCCTGTCAGTCTTCATGCTGTTGG cCAT-TAT TGTATCCTACTGGAAAGCTTCTGAGGGTGAGTAAA TTTACTCACCCTCAGAAGCTTTCCAGTAGGATACACCAACAGC 1869 ATGAAGACTGACAGGAT G GGAAGCCATGTTCTTAAGTGTAAT GACCACTGTATCATAAACCTCAGCCTGGATGGTAGG TGGCTTCC C ATCCTGTC 1870 GACAGGAT G GGAAGCCA 1871 Haemophilia A CTGAGGTTTATGATACAGTGGTCATTACACTTAAGAACATGGC 1872 Leu98Arg TTCCCATCCTGTCAGTC T TCATGCTGTTGGTGTATCCTACTGG CTT-CGT AAAGCTTCTGAGGGTGAGTAAAATACCCTCCTATT AATAGGAGGGTATTTTACTCACCCTCAGAAGCTTTCCAGTAGG 1873 ATACACCAACAGCATGA A GACTGACAGGATGGGAAGCCATGT TCTTAAGTGTAATGACCACTGTATCATAAACCTCAG TGTCAGTC T TCATGCTG 1874 CAGCATGA A GACTGACA 1875 Haemophilia A GATACAGTGGTCATTACACTTAAGAACATGGCTTCCCATCCTG 1876 Gly102Ser TCAGTCTTCATGCTGTT G GTGTATCCTACTGGAAAGCTTCTGA tGGT-AGT GGGTGAGTAAAATACCCTCCTATTGTCCTGTCATT AATGACAGGACAATAGGAGGGTATTTTACTCACCCTCAGAAG 1877 CTTTCCAGTAGGATACAC C AACAGCATGAAGACTGACAGGAT GGGAAGCCATGTTCTTAAGTGTAATGACCACTGTATC ATGCTGTT G GTGTATCC 1878 GGATACAC C AACAGCAT 1879 Haemophilia A CTTTGAGTGTACAGTGGATATAGAAAGGACAATTTTATTTCTTC 1880 Glu113Asp CTGCTATAGGAGCTGA A TATGATGATCAGACCAGTCAAAGGG GAAt-GAC AGAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGC GCTTCCACCAGGGAAGACTTTATCATCTTCTTTCTCCCTTTGA 1881 CTGGTCTGATCATCATA T TCAGCTCCTATAGCAGGAAGAAATA AAATTGTCCTTTCTATATCCACTGTACACTCAAAG GGAGCTGA A TATGATGA 1882 TCATCATA T TCAGCTCC 1883 Haemophilia A TTGAGTGTACAGTGGATATAGAAAGGACAATTTTATTTCTTCCT 1884 Tyr114Cys GCTATAGGAGCTGAAT A TGATGATCAGACCAGTCAAAGGGAG TAT-TGT AAAGAAGATGATAAAGTCTTCCCTGGTGGAAGCCA TGGCTTCCACCAGGGAAGACTTTATCATCTTCTTTCTCCCTTT 1885 GACTGGTCTGATCATCA T ATTCAGCTCCTATAGCAGGAAGAAA TAAATTGTCCTTTCTATATCCACTGTACACTCAA AGCTGAAT A TGATGATC 1886 GATCATCA T ATTCAGCT 1887 Haemophilia A GTACAGTGGATATAGAAAGGACAATTTTATTTCTTCCTGCTATA 1888 Asp116Gly GGAGCTGAATATGATG A TCAGACCAGTCAAAGGGAGAAAGAA GAT-GGT GATGATAAAGTCTTCCCTGGTGGAAGCCATACATA TATGTATGGCTTCCACCAGGGAAGACTTTATCATCTTCTTTCT 1889 CCCTTTGACTGGTCTGA T CATCATATTCAGCTCCTATAGCAGG AAGAAATAAAATTGTCCTTTCTATATCCACTGTAC ATATGATG A TCAGACCA 1890 TGGTCTGA T CATCATAT 1891 Haemophilia A ACAGTGGATATAGAAAGGACAATTTTATTTCTTCCTGCTATAG 1892 Gln117Term GAGCTGAATATGATGAT C AGACCAGTCAAAGGGAGAAAGAAG tCAG-TAG ATGATAAAGTCTTCCCTGGTGGAAGCCATACATATG CATATGTATGGCTTCCACCAGGGAAGACTTTATCATCTTCTTT 1893 CTCCCTTTGACTGGTCT G ATCATCATATTCAGCTCCTATAGCA GGAAGAAATAAAATTGTCCTTTCTATATCCACTGT ATGATGAT C AGACCAGT 1894 ACTGGTCT G ATCATCAT 1895 Haemophilia A TGGATATAGAAAGGACAATTTTATTTCTTCCTGCTATAGGAGC 1896 Thr118Ile TGAATATGATGATCAGA C CAGTCAAAGGGAGAAAGAAGATGA ACC-ATC TAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTG CAGACATATGTATGGCTTCCACCAGGGAAGACTTTATCATCTT 1897 CTTTCTCCCTTTGACTG G TCTGATCATCATATTCAGCTCCTAT AGCAGGAAGAAATAAAATTGTCCTTTCTATATCCA TGATCAGA C CAGTCAAA 1898 TTTGACTG G TCTGATCA 1899 Haemophilia A AGGACAATTTTATTTCTTCCTGCTATAGGAGCTGAATATGATG 1900 Glu122Term ATCAGACCAGTCAAAGG G AGAAAGAAGATGATAAAGTCTTCC gGAG-TAG CTGGTGGAAGCCATACATATGTCTGGCAGGTCCTGA TCAGGACCTGCCAGACATATGTATGGCTTCCACCAGGGAAGA 1901 CTTTATCATCTTCTTTCT C CCTTTGACTGGTCTGATCATCATAT TCAGCTCCTATAGCAGGAAGAAATAAAATTGTCCT GTCAAAGG G AGAAAGAA 1902 TTCTTTCT C CCTTTGAC 1903 Haemophilia A TTTCTTCCTGCTATAGGAGCTGAATATGATGATCAGACCAGTC 1904 Asp126His AAAGGGAGAAAGAAGAT G ATAAAGTCTTCCCTGGTGGAAGCC tGAT-CAT ATACATATGTCTGGCAGGTCCTGAAAGAGAATGGTC GACCATTCTCTTTCAGGACCTGCCAGACATATGTATGGCTTCC 1905 ACCAGGGAAGACTTTAT C ATCTTCTTTCTCCCTTTGACTGGTC TGATCATCATATTCAGCTCCTATAGCAGGAAGAAA AAGAAGAT G ATAAAGTC 1906 GACTTTAT C ATCTTCTT 1907 Haemophilia A AGTCAAAGGGAGAAAGAAGATGATAAAGTCTTCCCTGGTGGA 1908 Gln139Term AGCCATACATATGTCTGG C AGGTCCTGAAAGAGAATGGTCCA gCAG-TAG ATGGCCTCTGACCCACTGTGCCTTACCTACTCATATC GATATGAGTAGGTAAGGCACAGTGGGTCAGAGGCCATTGGA 1909 CCATTCTCTTTCAGGACCT G CCAGACATATGTATGGCTTCCAC CAGGGAAGACTTTATCATCTTCTTTCTCCCTTTGACT ATGTCTGG C AGGTCCTG 1910 CAGGACCT G CCAGACAT 1911 Haemophilia A AAAGGGAGAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGCC 1912 Val140Ala ATACATATGTCTGGCAGG T CCTGAAAGAGAATGGTCCAATGG GTC-GCC CCTCTGACCCACTGTGCCTTACCTACTCATATCTTTC GAAAGATATGAGTAGGTAAGGCACAGTGGGTCAGAGGCCATT 1913 GGACCATTCTCTTTCAGG A CCTGCCAGACATATGTATGGCTT CCACCAGGGAAGACTTTATCATCTTCTTTCTCCCTTT CTGGCAGG T CCTGAAAG 1914 CTTTCAGG A CCTGCCAG 1915 Haemophilia A AGATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTG 1916 Asn144Lys GCAGGTCCTGAAAGAGAA T GGTCCAATGGCCTCTGACCCACT AATg-AAA GTGCCTTACCTACTCATATCTTTCTCATGTGGACCTG CAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACAGTGG 1917 GTCAGAGGCCATTGGACC A TTCTCTTTCAGGACCTGCCAGAC ATATGTATGGCTTCCACCAGGGAAGACTTTATCATCT AAAGAGAA T GGTCCAAT 1918 ATTGGACC A TTCTCTTT 1919 Haemophilia AG ATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCA 1920 Gly145Asp GGTCCTGAAAGAGAATG G TCCAATGGCCTCTGACCCACTGTG GGT-GAT CCTTACCTACTCATATCTTTCTCATGTGGACCTGGT ACCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACAGT 1921 GGGTCAGAGGCCATTGGA C CATTCTCTTTCAGGACCTGCCAG ACATATGTATGGCTTCCACCAGGGAAGACTTTATCAT AGAGAATG G TCCAATGG 1922 CCATTGGA C CATTCTCT 1923 Haemophilia A ATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCA 1924 Gly145Val GGTCCTGAAAGAGAATG G TCCAATGGCCTCTGACCCACTGTG GGT-GTT CCTTACCTACTCATATCTTTCTCATGTGGACCTGGT ACCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACAGT 1925 GGGTCAGAGGCCATTGGA C CATTCTCTTTCAGGACCTGCCAG ACATATGTATGGCTTCCACCAGGGAAGACTTTATCAT AGAGAATG G TCCAATGG 1926 CCATTGGA C CATTCTCT 1927 Haemophilia A GATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCAG 1928 Pro146Ser GTCCTGAAAGAGAATGGT C CAATGGCCTCTGACCCACTGTGC tCCA-TCA CTTACCTACTCATATCTTTCTCATGTGGACCTGGTAA TTACCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACA 1929 GTGGGTCAGAGGCCATTG G ACCATTCTCTTTCAGGACCTGCC AGACATATGTATGGCTTCCACCAGGGAAGACTTTATC AGAATGGT C CAATGGCC 1930 GGCCATTG G ACCATTCT 1931 Haemophilia A CCATACATATGTCTGGCAGGTCCTGAAAGAGAATGGTCCAAT 1932 Cys153Trp GGCCTCTGACCCACTGTG C CTTACCTACTCATATCTTTCTCAT TGCc-TGG GTGGACCTGGTAAAAGACTTGAATTCAGGCCTCATT AATGAGGCCTGAATTCAAGTCTTTTACCAGGTCCACATGAGAA 1933 AGATATGAGTAGGTAAG G CACAGTGGGTCAGAGGCCATTGGA CCATTCTCTTTCAGGACCTGCCAGACATATGTATGG CCACTGTG C CTTACCTA 1934 TAGGTAAG G CACAGTGG 1935 Haemophilia A TGTCTGGCAGGTCCTGAAAGAGAATGGTCCAATGGCCTCTGA 1936 Tyr156Term CCCACTGTGCCTTACCTA C TCATATCTTTCTCATGTGGACCTG TACt-TAA GTAAAAGACTTGAATTCAGGCCTCATTGGAGCCCTA TAGGGCTCCAATGAGGCCTGAATTCAAGTCTTTTACCAGGTC 1937 CACATGAGAAAGATATGA G TAGGTAAGGCACAGTGGGTCAGA GGCCATTGGACCATTCTCTTTCAGGACCTGCCAGACA CTTACCTA C TCATATCT 1938 AGATATGA G TAGGTAAG 1939 Haemophilia A GTCTGGCAGGTCCTGAAAGAGAATGGTCCAATGGCCTCTGAC 1940 Ser157Pro CCACTGTGCCTTACCTAC T CATATCTTTCTCATGTGGACCTGG cTCA-CCA TAAAAGACTTGAATTCAGGCCTCATTGGAGCCCTAC GTAGGGCTCCAATGAGGCCTGAATTCAAGTCTTTTACCAGGT 1941 CCACATGAGAAAGATATG A GTAGGTAAGGCACAGTGGGTCAG AGGCCATTGGACCATTCTCTTTCAGGACCTGCCAGAC TTACCTAC T CATATCTT 1942 AAGATATG A GTAGGTAA 1943 Haemophilia A GTCCTGAAAGAGAATGGTCCAATGGCCTCTGACCCACTGTGC 1944 Ser160Pro CTTACCTACTCATATCTT T CTCATGTGGACCTGGTAAAAGACT tTCT-CCT TGAATTCAGGCCTCATTGGAGCCCTACTAGTATGTA TACATACTAGTAGGGCTCCAATGAGGCCTGAATTCAAGTCTTT 1945 TACCAGGTCCACATGAG A AAGATATGAGTAGGTAAGGCACAG TGGGTCAGAGGCCATTGGACCATTCTCTTTCAGGAC CATATCTT T CTCATGTG 1946 CACATGAG A AAGATATG 1947 Haemophilia A AAAGAGAATGGTCCAATGGCCTCTGACCCACTGTGCCTTACC 1948 Val162Met TACTCATATCTTTCTCAT G TGGACCTGGTAAAAGACTTGAATT tGTG-ATG CAGGCCTCATTGGAGCCCTACTAGTATGTAGAGAAG CTTCTCTACATACTAGTAGGGCTCCAATGAGGCCTGAATTCAA 1949 GTCTTTTACCAGGTCCA C ATGAGAAAGATATGAGTAGGTAAG GCACAGTGGGTCAGAGGCCATTGGACCATTCTCTTT TTTCTCAT G TGGACCTG 1950 CAGGTCCA C ATGAGAAA 1951 Haemophilia A CAATGGCCTCTGACCCACTGTGCCTTACCTACTCATATCTTTC 1952 Lys166Thr TCATGTGGACCTGGTAA A AGACTTGAATTCAGGCCTCATTGG AAA-ACA AGCCCTACTAGTATGTAGAGAAGGTAAGTGTATGAA TTCATACACTTACCTTCTCTACATACTAGTAGGGCTCCAATGA 1953 GGCCTGAATTCAAGTCT T TTACCAGGTCCACATGAGAAAGATA TGAGTAGGTAAGGCACAGTGGGTCAGAGGCCATTG CCTGGTAA A AGACTTGA 1954 TCAAGTCT T TTACCAGG 1955 Haemophilia A ACCCACTGTGCCTTACCTACTCATATCTTTCTCATGTGGACCT 1956 Ser170Leu GGTAAAAGACTTGAATT C AGGCCTCATTGGAGCCCTACTAGT TCA-TTA ATGTAGAGAAGGTAAGTGTATGAAAGCGTAGGATTG CAATCCTACGCTTTCATACACTTACCTTCTCTACATACTAGTAG 1957 GGCTCCAATGAGGCCT G AATTCAAGTCTTTTACCAGGTCCAC ATGAGAAAGATATGAGTAGGTAAGGCACAGTGGGT CTTGAATT C AGGCCTCA 1958 TGAGGCCT G AATTCAAG 1959 Haemophilia A AATGTTCTCACTTCTTTTTCAGGGAGTCTGGCCAAGGAAAAGA 1960 Phe195Val CACAGACCTTGCACAAA T TTATACTACTTTTTGCTGTATTTGAT aTTT-GTT GAAGGTTAGTGAGTCTTAATCTGAATTTTGGATT AATCCAAAATTCAGATTAAGACTCACTAACCTTCATCAAATACA 1961 GCAAAAAGTAGTATAA A TTTGTGCAAGGTCTGTGTCTTTTCCT TGGCCAGACTCCCTGAAAAAGAAGTGAGAACATT TGCACAAA T TTATACTA 1962 TAGTATAA A TTTGTGCA 1963 Haemophilia A CTTCTTTTTCAGGGAGTCTGGCCAAGGAAAAGACACAGACCT 1964 Leu198His TGCACAAATTTATACTAC T TTTTGCTGTATTTGATGAAGGTTAG CTT-CAT TGAGTCTTAATCTGAATTTTGGATTCCTGAAAGAA TTCTTTCAGGAATCCAAAATTCAGATTAAGACTCACTAACCTTC 1965 ATCAAATACAGCAAAA A GTAGTATAAATTTGTGCAAGGTCTGT GTCTTTTCCTTGGCCAGACTCCCTGAAAAAGAAG TATACTAC T TTTTGCTG 1966 CAGCAAAA A GTAGTATA 1967 Haemophilia A TTTCAGGGAGTCTGGCCAAGGAAAAGACACAGACCTTGCACA 1968 Ala200Asp AATTTATACTACTTTTTG C TGTATTTGATGAAGGTTAGTGAGTC GCT-GAT TTAATCTGAATTTTGGATTCCTGAAAGAAATCCTC GAGGATTTCTTTCAGGAATCCAAAATTCAGATTAAGACTCACT 1969 AACCTTCATCAAATACA G CAAAAAGTAGTATAAATTTGTGCAA GGTCTGTGTCTTTTCCTTGGCCAGACTCCCTGAAA ACTTTTTG C TGTATTTG 1970 CAAATACA G CAAAAAGT 1971 Haemophilia A TTTTCAGGGAGTCTGGCCAAGGAAAAGACACAGACCTTGCAC 1972 Ala200Thr AAATTTATACTACTTTTT G CTGTATTTGATGAAGGTTAGTGAGT tGCT-ACT CTTAATCTGAATTTTGGATTCCTGAAAGAAATCCT AGGATTTCTTTCAGGAATCCAAAATTCAGATTAAGACTCACTA 1973 ACCTTCATCAAATACAG C AAAAAGTAGTATAAATTTGTGCAAG GTCTGTGTCTTTTCCTTGGCCAGACTCCCTGAAAA TACTTTTT G CTGTATTT 1974 AAATACAG C AAAAAGTA 1975 Haemophilia A AACTCCTTGATGCAGGATAGGGATGCTGCATCTGCTCGGGCC 1976 Val234Phe TGGCCTAAAATGCACACA G TCAATGGTTATGTAAACAGGTCTC aGTC-TTC TGCCAGGTATGTACACACCTGCTCAACAATCCTCAG CTGAGGATTGTTGAGCAGGTGTGTACATACCTGGCAGAGACC 1977 TGTTTACATAACCATTGA C TGTGTGCATTTTAGGCCAGGCCCG AGCAGATGCAGCATCCCTATCCTGCATCAAGGAGTT TGCACACA G TCAATGGT 1978 ACCATTGA C TGTGTGCA 1979 Haemophilia A ATTTCAGATTCTCTACTTCATAGCCATAGGTGTCTTATTCCTAC 1980 Gly247Glu TTTACAGGTCTGATTG G ATGCCACAGGAAATCAGTCTATTGGC GGA-GAA ATGTGATTGGAATGGGCACCACTCCTGAAGTGCA TGCACTTCAGGAGTGGTGCCCATTCCAATCACATGCCAATAG 1981 ACTGATTTCCTGTGGCAT C CAATCAGACCTGTAAAGTAGGAAT AAGACACCTATGGCTATGAAGTAGAGAATCTGAAAT TCTGATTG G ATGCCACA 1982 TGTGGCAT C CAATCAGA 1983 Haemophilia A ATAGGTGTCTTATTCCTACTTTACAGGTCTGATTGGATGCCAC 1984 Trp255Cys AGGAAATCAGTCTATTG G CATGTGATTGGAATGGGCACCACT TGGc-TGT CCTGAAGTGCACTCAATATTCCTCGAAGGTCACACA TGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGGT 1985 GCCCATTCCAATCACATG C CAATAGACTGATTTCCTGTGGCAT CCAATCAGACCTGTAAAGTAGGAATAAGACACCTAT GTCTATTG G CATGTGAT 1986 ATCACATG C CAATAGAC 1987 Haemophilia A ATAGGTGTCTTATTCCTACTTTACAGGTCTGATTGGATGCCAC 1988 Trp255Term AGGAAATCAGTCTATTG G CATGTGATTGGAATGGGCACCACT TGGc-TGA CCTGAAGTGCACTCAATATTCCTCGAAGGTCACACA TGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGGT 1989 GCCCATTCCAATCACATG C CAATAGACTGATTTCCTGTGGCAT CCAATCAGACCTGTAAAGTAGGAATAAGACACCTAT GTCTATTG G CATGTGAT 1990 ATCACATG C CAATAGAC 1991 Haemophilia A AGGTGTCTTATTCCTACTTTACAGGTCTGATTGGATGCCACAG 1992 His256Leu GAAATCAGTCTATTGGC A TGTGATTGGAATGGGCACCACTCC CAT-CTT TGAAGTGCACTCAATATTCCTCGAAGGTCACACATT AATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTG 1993 GTGCCCATTCCAATCACA T GCCAATAGACTGATTTCCTGTGG CATCCAATCAGACCTGTAAAGTAGGAATAAGACACCT CTATTGGC A TGTGATTG 1994 CAATCACA T GCCAATAG 1995 Haemophilia A TATTCCTACTTTACAGGTCTGATTGGATGCCACAGGAAATCAG 1996 Gly259Arg TCTATTGGCATGTGATT G GAATGGGCACCACTCCTGAAGTGC tGGA-AGA ACTCAATATTCCTCGAAGGTCACACATTTCTTGTGA TCACAAGAAATGTGTGACCTTCGAGGAATATTGAGTGCACTTC 1997 AGGAGTGGTGCCCATTC C AATCACATGCCAATAGACTGATTT CCTGTGGCATCCAATCAGACCTGTAAAGTAGGAATA ATGTGATT G GAATGGGC 1998 GCCCATTC C AATCACAT 1999 Haemophilia A TTGGATGCCACAGGAAATCAGTCTATTGGCATGTGATTGGAAT 2000 Val266Gly GGGCACCACTCCTGAAG T GCACTCAATATTCCTCGAAGGTCA GTG-GGG CACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTT AAGGACGCCTGGCGATGGTTCCTCACAAGAAATGTGTGACCT 2001 TCGAGGAATATTGAGTGC A CTTCAGGAGTGGTGCCCATTCCA ATCACATGCCAATAGACTGATTTCCTGTGGCATCCAA TCCTGAAG T GCACTCAA 2002 TTGAGTGC A CTTCAGGA 2003 Haemophilia A CAGTCTATTGGCATGTGATTGGAATGGGCACCACTCCTGAAG 2004 Glu272Gly TGCACTCAATATTCCTCG A AGGTCACACATTTCTTGTGAGGAA GAA-GGA CCATCGCCAGGCGTCCTTGGAAATCTCGCCAATAAC GTTATTGGCGAGATTTCCAAGGACGCCTGGCGATGGTTCCTC 2005 ACAAGAAATGTGTGACCT T CGAGGAATATTGAGTGCACTTCAG GAGTGGTGCCCATTCCAATCACATGCCAATAGACTG ATTCCTCG A AGGTCACA 2006 TGTGACCT T CGAGGAAT 2007 Haemophilia A TCAGTCTATTGGCATGTGATTGGAATGGGCACCACTCCTGAA 2008 Glu272Lys GTGCACTCAATATTCCTC G AAGGTCACACATTTCTTGTGAGGA cGAA-AAA ACCATCGCCAGGCGTCCTTGGAAATCTCGCCAATAA TTATTGGCGAGATTTCCAAGGACGCCTGGCGATGGTTCCTCA 2009 CAAGAAATGTGTGACCTT C GAGGAATATTGAGTGCACTTCAG GAGTGGTGCCCATTCCAATCACATGCCAATAGACTGA TATTCCTC G AAGGTCAC 2010 GTGACCTT C GAGGAATA 2011 Haemophilia A GGCATGTGATTGGAATGGGCACCACTCCTGAAGTGCACTCAA 2012 Thr275Ile TATTCCTCGAAGGTCACA C ATTTCTTGTGAGGAACCATCGCCA ACA-ATA GGCGTCCTTGGAAATCTCGCCAATAACTTTCCTTAC GTAAGGAAAGTTATTGGCGAGATTTCCAAGGACGCCTGGCGA 2013 TGGTTCCTCACAAGAAAT G TGTGACCTTCGAGGAATATTGAGT GCACTTCAGGAGTGGTGCCCATTCCAATCACATGCC AGGTCACA C ATTTCTTG 2014 CAAGAAAT G TGTGACCT 2015 Haemophilia A TTGGAATGGGCACCACTCCTGAAGTGCACTCAATATTCCTCG 2016 Val278Ala AAGGTCACACATTTCTTG T GAGGAACCATCGCCAGGCGTCCT GTG-GCG TGGAAATCTCGCCAATAACTTTCCTTACTGCTCAAAC GTTTGAGCAGTAAGGAAAGTTATTGGCGAGATTTCCAAGGAC 2017 GCCTGGCGATGGTTCCTC A CAAGAAATGTGTGACCTTCGAGG AATATTGAGTGCACTTCAGGAGTGGTGCCCATTCCAA ATTTCTTG T GAGGAACC 2018 GGTTCCTC A CAAGAAAT 2019 Haemophilia A TGGGCACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTC 2020 Asn280Ile ACACATTTCTTGTGAGGA A CCATCGCCAGGCGTCCTTGGAAA AAC-ATC TCTCGCCAATAACTTTCCTTACTGCTCAAACACTCTT AAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGATTTCCA 2021 AGGACGCCTGGCGATGG T TCCTCACAAGAAATGTGTGACCTT CGAGGAATATTGAGTGCACTTCAGGAGTGGTGCCCA TGTGAGGA A CCATCGCC 2022 GGCGATGG T TCCTCACA 2023 Haemophilia A ACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACAT 2024 Arg282Cys TTCTTGTGAGGAACCAT C GCCAGGCGTCCTTGGAAATCTCGC tCGC-TGC CAATAACTTTCCTTACTGCTCAAACACTCTTGATGG CCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGA 2025 TTTCCAAGGACGCCTGGC G ATGGTTCCTCACAAGAAATGTGT GACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGGT GGAACCAT C GCCAGGCG 2026 CGCCTGGC G ATGGTTCC 2027 Haemophilia A CCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATT 2028 Arg282His TCTTGTGAGGAACCATC G CCAGGCGTCCTTGGAAATCTCGCC CGC-CAC AATAACTTTCCTTACTGCTCAAACACTCTTGATGGA TCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAG 2029 ATTTCCAAGGACGCCTGG C GATGGTTCCTCACAAGAAATGTG TGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGG GAACCATC G CCAGGCGT 2030 ACGCCTGG C GATGGTTC 2031 Haemophilia A CCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATT 2032 Arg282Leu TCTTGTGAGGAACCATC G CCAGGCGTCCTTGGAAATCTCGCC CGC-CTC AATAACTTTCCTTACTGCTCAAACACTCTTGATGGA TCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAG 2033 ATTTCCAAGGACGCCTGG C GATGGTTCCTCACAAGAAATGTG TGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGG GAACCATC G CCAGGCGT 2034 ACGCCTGG C GATGGTTC 2035 Haemophilia A CTGAAGTGCACTCAATATTCCTCGAAGGTCACACATTTCTTGT 2036 Ala284Glu GAGGAACCATCGCCAGG C GTCCTTGGAAATCTCGCCAATAAC GCG-GAG TTTCCTTACTGCTCAAACACTCTTGATGGACCTTGG CCAAGGTCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATT 2037 GGCGAGATTTCCAAGGAC G CCTGGCGATGGTTCCTCACAAG AAATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAG TCGCCAGG C GTCCTTGG 2038 CCAAGGAC G CCTGGCGA 2039 Haemophilia A CCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATTTCTTG 2040 Ala284Pro TGAGGAACCATCGCCAG G CGTCCTTGGAAATCTCGCCAATAA gGCG-CCG CTTTCCTTACTGCTCAAACACTCTTGATGGACCTTG CAAGGTCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTG 2041 GCGAGATTTCCAAGGACG C CTGGCGATGGTTCCTCACAAGAA ATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGG ATCGCCAG G CGTCCTTG 2042 CAAGGACG C CTGGCGAT 2043 Haemophilia A TATTCCTCGAAGGTCACACATTTCTTGTGAGGAACCATCGCCA 2044 Ser289Leu GGCGTCCTTGGAAATCT C GCCAATAACTTTCCTTACTGCTCAA TCG-TTG ACACTCTTGATGGACCTTGGACAGTTTCTACTGTT AACAGTAGAAACTGTCCAAGGTCCATCAAGAGTGTTTGAGCA 2045 GTAAGGAAAGTTATTGGC G AGATTTCCAAGGACGCCTGGCGA TGGTTCCTCACAAGAAATGTGTGACCTTCGAGGAATA GGAAATCT C GCCAATAA 2046 TTATTGGC G AGATTTCC 2047 Haemophilia A GTCACACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGG 2048 Phe293Ser AAATCTCGCCAATAACTT T CCTTACTGCTCAAACACTCTTGAT TTC-TCC GGACCTTGGACAGTTTCTACTGTTTTGTCATATCTC GAGATATGACAAAACAGTAGAAACTGTCCAAGGTCCATCAAG 2049 AGTGTTTGAGCAGTAAGG A AAGTTATTGGCGAGATTTCCAAG GACGCCTGGCGATGGTTCCTCACAAGAAATGTGTGAC AATAACTT T CCTTACTG 2050 CAGTAAGG A AAGTTATT 2051 Haemophilia A ACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATC 2052 Thr295Ala TCGCCAATAACTTTCCTT A CTGCTCAAACACTCTTGATGGACC tACT-GCT TTGGACAGTTTCTACTGTTTTGTCATATCTCTTCCC GGGAAGAGATATGACAAAACAGTAGAAACTGTCCAAGGTCCA 2053 TCAAGAGTGTTTGAGCAG T AAGGAAAGTTATTGGCGAGATTTC CAAGGACGCCTGGCGATGGTTCCTCACAAGAAATGT CTTTCCTT A CTGCTCAA 2054 TTGAGCAG T AAGGAAAG 2055 Haemophilia A CATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATCT 2056 Thr295Ile CGCCAATAACTTTCCTTA C TGCTCAAACACTCTTGATGGACCT ACT-ATT TGGACAGTTTCTACTGTTTTGTCATATCTCTTCCCA TGGGAAGAGATATGACAAAACAGTAGAAACTGTCCAAGGTCC 2057 ATCAAGAGTGTTTGAGCA G TAAGGAAAGTTATTGGCGAGATTT CCAAGGACGCCTGGCGATGGTTCCTCACAAGAAATG TTTCCTTA C TGCTCAAA 2058 TTTGAGCA G TAAGGAAA 2059 Haemophilia A TTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATCTCGC 2060 Ala296Val CAATAACTTTCCTTACTG C TCAAACACTCTTGATGGACCTTGG GCT-GTT ACAGTTTCTACTGTTTTGTCATATCTCTTCCCACCA TGGTGGGAAGAGATATGACAAAACAGTAGAAACTGTCCAAGG 2061 TCCATCAAGAGTGTTTGA G CAGTAAGGAAAGTTATTGGCGAG ATTTCCAAGGACGCCTGGCGATGGTTCCTCACAAGAA CCTTACTG C TCAAACAC 2062 GTGTTTGA G CAGTAAGG 2063 Haemophilia A TCTCGCCAATAACTTTCCTTACTGCTCAAACACTCTTGATGGA 2064 Leu308Pro CCTTGGACAGTTTCTAC T GTTTTGTCATATCTCTTCCCACCAA CTG-CCG CATGGTAATATCTTGGATCTTTAAAATGAATATTA TAATATTCATTTTAAAGATCCAAGATATTACCATGTTGGTGGGA 2065 AGAGATATGACAAAAC A GTAGAAACTGTCCAAGGTCCATCAA GAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGA GTTTCTAC T GTTTTGTC 2066 GACAAAAC A GTAGAAAC 2067 Haemophilia A ACAGCCTAATATAGCAAGACACTCTGACATTGTTTGGTTTGTC 2068 Glu321Lys TGACTCCAGATGGCATG G AAGCTTATGTCAAAGTAGACAGCT gGAA-AAA GTCCAGAGGAACCCCAACTACGAATGAAAAATAATG CATTATTTTTCATTCGTAGTTGGGGTTCCTCTGGACAGCTGTC 2069 TACTTTGACATAAGCTT C CATGCCATCTGGAGTCAGACAAACC AAACAATGTCAGAGTGTCTTGCTATATTAGGCTGT ATGGCATG G AAGCTTAT 2070 ATAAGCTT C CATGCCAT 2071 Haemophilia A ATATAGCAAGACACTCTGACATTGTTTGGTTTGTCTGACTCCA 2072 Tyr323Term GATGGCATGGAAGCTTA T GTCAAAGTAGACAGCTGTCCAGAG TATg-TAA GAACCCCAACTACGAATGAAAAATAATGAAGAAGCG CGCTTCTTCATTATTTTTCATTCGTAGTTGGGGTTCCTCTGGA 2073 CAGCTGTCTACTTTGAC A TAAGCTTCCATGCCATCTGGAGTCA GACAAACCAAACAATGTCAGAGTGTCTTGCTATAT GAAGCTTA T GTCAAAGT 2074 ACTTTGAC A TAAGCTTC 2075 Haemophilia A AAGACACTCTGACATTGTTTGGTTTGTCTGACTCCAGATGGCA 2076 Val326Leu TGGAAGCTTATGTCAAA G TAGACAGCTGTCCAGAGGAACCCC aGTA-CTA AACTACGAATGAAAAATAATGAAGAAGCGGAAGACT AGTCTTCCGCTTCTTCATTATTTTTCATTCGTAGTTGGGGTTC 2077 CTCTGGACAGCTGTCTA C TTTGACATAAGCTTCCATGCCATCT GGAGTCAGACAAACCAAACAATGTCAGAGTGTCTT ATGTCAAA G TAGACAGC 2078 GCTGTCTA C TTTGACAT 2079 Haemophilia A TGACATTGTTTGGTTTGTCTGACTCCAGATGGCATGGAAGCTT 2080 Cys329Arg ATGTCAAAGTAGACAGC T GTCCAGAGGAACCCCAACTACGAA cTGT-CGT TGAAAAATAATGAAGAAGCGGAAGACTATGATGATG CATCATCATAGTCTTCCGCTTCTTCATTATTTTTCATTCGTAGT 2081 TGGGGTTCCTCTGGAC A GCTGTCTACTTTGACATAAGCTTCC ATGCCATCTGGAGTCAGACAAACCAAACAATGTCA TAGACAGC T GTCCAGAG 2082 CTCTGGAC A GCTGTCTA 2083 Haemophilia A GACATTGTTTGGTTTGTCTGACTCCAGATGGCATGGAAGCTTA 2084 Cys329Tyr TGTCAAAGTAGACAGCT G TCCAGAGGAACCCCAACTACGAAT TGT-TAT GAAAAATAATGAAGAAGCGGAAGACTATGATGATGA TCATCATCATAGTCTTCCGCTTCTTCATTATTTTTCATTCGTAG 2085 TTGGGGTTCCTCTGGA C AGCTGTCTACTTTGACATAAGCTTCC ATGCCATCTGGAGTCAGACAAACCAAACAATGTC AGACAGCT G TCCAGAGG 2086 CCTCTGGA C AGCTGTCT 2087 Haemophilia A ACTCCAGATGGCATGGAAGCTTATGTCAAAGTAGACAGCTGT 2088 Arg336Term CCAGAGGAACCCCAACTA C GAATGAAAAATAATGAAGAAGCG aCGA-TGA GAAGACTATGATGATGATCTTACTGATTCTGAAATGG CCATTTCAGAATCAGTAAGATCATCATCATAGTCTTCCGCTTC 2089 TTCATTATTTTTCATTC G TAGTTGGGGTTCCTCTGGACAGCTG TCTACTTTGACATAAGCTTCCATGCCATCTGGAGT CCCAACTA C GAATGAAA 2090 TTTCATTC G TAGTTGGG 2091 Haemophilia A GATTCTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTC 2092 Arg372Cys CTTCCTTTATCCAAATT C GCTCAGTTGCCAAGAAGCATCCTAA tCGC-TGC AACTTGGGTACATTACATTGCTGCTGAAGAGGAGG CCTCCTCTTCAGCAGCAATGTCAATGTACCCAAGTTTTAGGATG 2093 CTTCTTGGCAACTGAGC G AATTTGGATAAAGGAAGGAGAGTT GTCATCATCAAACCTGACCACATCCATTTCAGAATC TCCAAATT C GCTCAGTT 2094 AACTGAGC G AATTTGGA 2095 Haemophilia A ATTCTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCC 2096 Arg372His TTCCTTTATCCAAATTC G CTCAGTTGCCAAGAAGCATCCTAAA CGC-CAC ACTTGGGTACATTACATTGCTGCTGAAGAGGAGGA TCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAGGAT 2097 GCTTCTTGGCAACTGAG C GAATTTGGATAAAGGAAGGAGAGT TGTCATCATCAAACCTGACCACATCCATTTCAGAAT CCAAATTC G CTCAGTTG 2098 CAACTGAG C GAATTTGG 2099 Haemophilia A CTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCCTTC 2100 Ser373Leu CTTTATCCAAATTCGCT C AGTTGCCAAGAAGCATCCTAAAACT TCA-TTA TGGGTACATTACATTGCTGCTGAAGAGGAGGACTG CAGTCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAG 2101 GATGCTTCTTGGCAACT G AGCGAATTTGGATAAAGGAAGGAG AGTTGTCATCATCAAACCTGACCACATCCATTTCAG AATTCGCT C AGTTGCCA 2102 TGGCAACT G AGCGAATT 2103 Haemophilia A TCTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCCTT 2104 Ser373Pro CCTTTATCCAAATTCGC T CAGTTGCCAAGAAGCATCCTAAAAC cTCA-CCA TTGGGTACATTACATTGCTGCTGAAGAGGAGGACT AGTCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAGG 2105 ATGCTTCTTGGCAACTG A GCGAATTTGGATAAAGGAAGGAGA GTTGTCATCATCAAACCTGACCACATCCATTTCAGA AAATTCGC T CAGTTGCC 2106 GGCAACTG A GCGAATTT 2107 Haemophilia A CTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCCTTC 2108 Ser373Term CTTTATCCAAATTCGCT C AGTTGCCAAGAAGCATCCTAAAACT TCA-TAA TGGGTACATTACATTGCTGCTGAAGAGGAGGACTG CAGTCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAG 2109 GATGCTTCTTGGCAACT G AGCGAATTTGGATAAAGGAAGGAG AGTTGTCATCATCAAACCTGACCACATCCATTTCAG ATTCGCT C AGTTGCCA 2110 TGGCAACTGAGCGAATT 2111 Haemophilia A CCTTCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTA 2112 Ile386Phe AAACTTGGGTACATTAC A TTGCTGCTGAAGAGGAGGACTGGG cATT-TTT ACTATGCTCCCTTAGTCCTCGCCCCCGATGACAGGT ACCTGTCATCGGGGGCGAGGACTAAGGGAGCATAGTCCCAG 2113 TCCTCCTCTTCAGCAGCAA T GTAATGTACCCAAGTTTTAGGAT GCTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAGG TACATTAC A TTGCTGCT 2114 AGCAGCAA T GTAATGTA 2115 Haemophilia A CTTCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTAA 2116 Ile386Ser AACTTGGGTACATTACA T TGCTGCTGAAGAGGAGGACTGGGA ATT-AGT CTATGCTCCCTTAGTCCTCGCCCCCGATGACAGGTA TACCTGTCATCGGGGGCGAGGACTAAGGGAGCATAGTCCCA 2117 GTCCTCCTCTTCAGCAGCAI A TGTAATGTACCCAAGTTTTAGGA TGCTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAG ACATTACA T TGCTGCTG 2118 CAGCAGCA A TGTAATGT 2119 Haemophilia A AAATTCGCTCAGTTGCCAAGAAGCATCCTAAAACTTGGGTACA 2120 Glu390Gly TTACATTGCTGCTGAAG A GGAGGACTGGGACTATGCTCCCTT GAG-GGG AGTCCTCGCCCCCGATGACAGGTAAGCACTTTTTGA TCAAAAAGTGCTTACCTGTCATCGGGGGCGAGGACTAAGGGA 2121 GCATAGTCCCAGTCCTCC T CTTCAGCAGCAATGTAATGTACC CAAGTTTTAGGATGCTTCTTGGCAACTGAGCGAATTT TGCTGAAG A GGAGGACT 2122 AGTCCTCC T CTTCAGCA 2123 Haemophilia A TCAGTTGCCAAGAAGCATCCTAAAACTTGGGTACATTACATTG 2124 Trp393Gly CTGCTGAAGAGGAGGAC T GGGACTATGCTCCCTTAGTCCTCG cTGG-GGG CCCCCGATGACAGGTAAGCACTTTTTGACTATTGGT ACCAATAGTCAAAAAGTGCTTACCTGTCATCGGGGGCGAGGA 2125 CTAAGGGAGCATAGTCCC A GTCCTCCTCTTCAGCAGCAATGT AATGTACCCAAGTTTTAGGATGCTTCTTGGCAACTGA AGGAGGAC T GGGACTAT 2126 ATAGTCCC A GTCCTCCT 2127 Haemophilia A GCCTACCTAGAATTTTTCTTCCCAACCTCTCATCTTTTTTTCTC 2128 Lys408Ile TTATACAGAAGTTATA A AAGTCAATATTTGAACAATGGCCCTC AAA-ATA AGCGGATTGGTAGGAAGTACAAAAAAGTCCGATT AATCGGACTTTTTTGTACTTCCTACCAATCCGCTGAGGGCCAT 2129 TGTTCAAATATTGACTT T TATAACTTCTGTATAAGAGAAAAAAA GATGAGAGGTTGGGAAGAAAAATTCTAGGTAGGC AAGTTATA A AAGTCAAT 2130 ATTGACTT T TATAACTT 2131 Haemophilia A TTTTCTTCCCAACCTCTCATCTTTTTTTCTCTTATACAGAAGTT 2132 Leu412Phe ATAAAAGTCAATATTT G AACAATGGCCCTCAGCGGATTGGTAG TTGa-TTT GAAGTACAAAAAAGTCCGATTTATGGCATACACA TGTGTATGCCATAAATCGGACTTTTTTGTACTTCCTACCAATC 2133 CGCTGAGGGCCATTGTT C AAATATTGACTTTTATAACTTCTGT ATAAGAGAAAAAAAGATGAGAGGTTGGGAAGAAAA CAATATTT G AACAATGG 2134 CCATTGTT C AAATATTG 2135 Haemophilia A TCATCTTTTTTTCTCTTATACAGAAGTTATAAAAGTCAATATTTG 2136 Arg418Trp AACAATGGCCCTCAG C GGATTGGTAGGAAGTACAAAAAAGTC gCGG-TGG CGATTTATGGCATACACAGATGAAACCTTTAAGA TCTTAAAGGTTTCATCTGTGTATGCCATAAATCGGACTTTTTTG 2137 TACTTCCTACCAATCC G CTGAGGGCCATTGTTCAAATATTGAC TTTATAACTTCTGTATAAGAGAAAAAAAGATGA GCCCTCAG C GGATTGGT 2138 ACCAATCC G CTGAGGGC 2139 Haemophilia A TTTTTCTCTTATACAGAAGTTATAAAAGTCAATATTTGAACAAT 2140 Gly420Val GGCCCTCAGCGGATTG G TAGGAAGTACAAAAAAGTCCGATTT GGT-GTT ATGGCATACACAGATGAAACCTTTAAGACTCGTGA TCACGAGTCTTAAAGGTTTCATCTGTGTATGCCATAAATCGGA 2141 CTTTTTTGTACTTCCTA C CAATCCGCTGAGGGCCATTGTTCAA ATATTGGACTTTTATAACTTCTGTATAAGAGAAAAA GCGGATTG G TAGGAAGT 2142 ACTTCCTA C CAATCCGC 2143 Haemophilia A GAAGTTATAAAAGTCAATATTTGAACAATGGCCCTCAGCGGAT 2144 Lys425Arg TGGTAGGAAGTACAAAA A AGTCCGATTTATGGCATACACAGAT AAA-AGA GAAACCTTTAAGACTCGTGAAGCTATTCAGCATGA TCATGCTGAATAGCTTCACGAGTCTTAAAGGTTTCATCTGTGT 2145 ATGCCATAAATCGGACT T TTTTGTACTTCCTACCAATCCGCTG AGGGCCATTGTTCAAATATTGACTTTTATAACTTC GTACAAAA A AGTCCGAT 2146 ATCGGACT T TTTTGTAC 2147 Haemophilia A TATAAAAGTCAATATTTGAACAATGGCCCTCAGCGGATTGGTA 2148 Arg427Term GGAAGTACAAAAAAGTC C GATTTATGGCATACACAGATGAAAC cCGA-TGA CTTTAAGACTCGTGAAGCTATTCAGCATGAATCAG CTGATTCATGCTGAATAGCTTCACGAGTCTTAAAGGTTTCATC 2149 TGTGTATGCCATAAATC G GACTTTTTTGTACTTCCTACCAATC CGCTGAGGGCCATTGTTCAAATATTGACTTTTATA AAAAAGTC C GATTTATG 2150 CATAAATC G GACTTTTT 2151 Haemophilia A TATTTGAACAATGGCCCTCAGCGGATTGGTAGGAAGTACAAA 2152 Tyr431Asn AAAGTCCGATTTATGGCA T ACACAGATGAAACCTTTAAGACTC aTAC-AAC GTGAAGCTATTCAGCATGAATCAGGAATCTTGGGAC GTCCCAAGATTCCTGATTCATGCTGAATAGCTTCACGAGTCTT 2153 AAAGGTTTCATCTGTGT A TGCCATAAATCGGACTTTTTTGTAC TTCCTACCAATCCGCTGAGGGCCATTGTTCAAATA TTATGGCA T ACACAGAT 2154 ATCTGTGT A TGCCATAA 2155 Haemophilia A GCCCTCAGCGGATTGGTAGGAAGTACAAAAAAGTCCGATTTA 2156 Thr435Ile TGGCATACACAGATGAAA C CTTTAAGACTCGTGAAGCTATTCA ACC-ATC GCATGAATCAGGAATCTTGGGACCTTTACTTTATGG CCATAAAGTAAAGGTCCCAAGATTCCTGATTCATGCTGAATAG 2157 CTTCACGAGTCTTAAAG G TTTCATCTGTGTATGCCATAAATCG GACTTTTTTGTACTTCCTACCAATCCGCTGAGGGC AGATGAAA C CTTTAAGA 2158 TCTTAAAG G TTTCATCT 2159 Haemophilia A ACACAGATGAAACCTTTAAGACTCGTGAAGCTATTCAGCATGA 2160 Pro451Leu ATCAGGAATCTTGGGAC C TTTACTTTATGGGGAAGTTGGAGA CCT-CTT CACACTGTTGGTAAGTTGAAGAAAAGATTTAAGGTC GACCTTAAATCTTTTCTTCAACTTACCAACAGTGTGTCTCCAA 2161 CTTCCCCATCAAAGTAAA G GTCCCAAGATTCCTGATTCATGCTG AATAGCTTCACGAGTCTTAAAGGTTTCATCTGTGT CTTGGGAC C TTTACTTT 2162 AAAGTAAA G GTCCCAAG 2163 Haemophilia A TACACAGATGAAACCTTTAAGACTCGTGAAGCTATTCAGCATG 2164 Pro451Thr AATCAGGAATCTTGGGA C CTTTACTTTATGGGGAAGTTGGAGA aCCT-ACT CACACTGTTGGTAAGTTGAAGAAAAGATTTAAGGT ACCTTAAATCTTTTCTTCAACTTACCAACAGTGTGTCTCCAACT 2165 TCCCCATAAAGTAAAG G TCCCAAGATTCCTGATTCATGCTGAA TAGCTTCACGAGTCTTAAAGGTTTCATCTGTGTA TCTTGGGA C CTTTACTT 2166 AAGTAAAG G TCCCAAGA 2167 Haemophilia A ACCTTTAAGACTCGTGAAGCTATTCAGCATGAATCAGGAATCT 2168 Gly455Arg TGGGACCTTTACTTTAT G GGGAAGTTGGAGACACACTGTTGG tGGG-AGG TAAGTTGAAGAAAAGATTTAAGGTCAGGTAAGAAGA TCTTCTTACCTGACCTTAAATCTTTTCTTCAACTTACCAACAGT 2169 GTGTCTCCAACTTCCC C ATAAAGTAAAGGTCCCAAGATTCCTG ATTCATGCTGAATAGCTTCACGAGTCTTAAAGGT TACTTTAT G GGGAAGTT 2170 AACTTCCC C ATAAAGTA 2171 Haemophilia A CCTTTAAGACTCGTGAAGCTATTCAGCATGAATCAGGAATCTT 2172 Gly455Glu GGGACCTTTACTTTATG G GGAAGTTGGAGACACACTGTTGGT GGG-GAG AAGTTGAAGAAAAGATTTAAGGTCAGGTAAGAAGAA TTCTTCTTACCTGACCTTAAATCTTTTCTTCAACTTACCAACAG 2173 TGTGTCTCCAACTTCC C ATAAAGTAAAGGTCCCAAGATTCCT GATTCATGCTGAATAGCTTCACGAGTCTTAAAGG ACTTTATG G GGAAGTTG 2174 CAACTTCC C CATAAAGT 2175 Haemophilia A CGTGAAGCTATTCAGCATGAATCAGGAATCTTGGGACCTTTAC 2176 Asp459Asn TTTATGGGGAAGTTGGA G ACACACTGTTGGTAAGTTGAAGAA aGAC-AAC AAGATTTAAGGTCAGGTAAGAAGAAAAAGTCTGGAG CTCCAGACTTTTTCTTCTTACCTGACCTTAAATCTTTTCTTCAA 2177 CTTACCAACAGTGTGT C TCCAACTTCCCCATAAAGTAAAGGTC CCAAGATTCCTGATTCATGCTGAATAGCTTCACG AAGTTGGA G ACACACTG 2178 CAGTGTGT C TCCAACTT 2179 Haemophilia A TGTTGATCCTAGTCGTTTTAGGATTTGATCTTAGATCTCGCTTA 2180 Phe465Cys TACTTTCAGATTATAT T TAAGAATCAAGCAAGCAGACCATATAA TTT-TGT CATCTACCCTCACGGAATCACTGATGTCCGTCC GGACGGACATCAGTGATTCCGTGAGGGTAGATGTTATATGGT 2181 CTGCTTGCTTGATTCTTA A ATATAATCTGAAAGTATAAGCGAG ATCTAAGATCAAATCCTAAAACGACTAGGATCAACA GATTATAT T TAAGAATC 2182 GATTCTTA A ATATAATC 2183 Haemophilia A TCGTTTTAGGATTTGATCTTAGATCTCGCTTATACTTTCAGATT 2184 Ala469Gly ATATTTAAGAATCAAG C AAGCAGACCATATAACATCTACCCTC GCA-GGA ACGGAATCACTGATGTCCGTCCTTTGTATTCAAG CTTGAATACAAAGGACGGACATCAGTGATTCCGTGAGGGTAG 2185 ATGTTATATGGTCTGCTT G CTTGATTCTTAAATATAATCTGAAA GTATAAGCGAGATCTAAGATCAAATCCTAAAACGA GAATCAAG C AAGCAGAC 2186 GTCTGCTT G CTTGATTC 2187 Haemophilia A TTAGGATTTGATCTTAGATCTCGCTTATACTTTCAGATTATATT 2188 Arg471Gly TAAGAATCAAGCAAGC A GACCATATAACATCTACCCTCACGG cAGA-GGA AATCACTGATGTCCGTCCTTTGTATTCAAGGAGAT ATCTCCTTGAATACAAAGGACGGACATCAGTGATTCCGTGAG 2189 GGTAGATGTTATATGGTC T GCTTGCTTGATTCTTAAATATAATC TGAAAGTATAAGCGAGATCTAAGATCAAATCCTAA AAGCAAGC A GACCATAT 2190 ATATGGTC T GCTTGCTT 2191 Haemophilia A TTGATCTTAGATCTCGCTTATACTTTCAGATTATATTTAAGAAT 2192 Tyr473Cys CAAGCAAGCAGACCAT A TAACATCTACCCTCACGGAATCACT TAT-TGT GATGTCCGTCCTTTGTATTCAAGGAGATTACCAAA TTTGGTAATCTCCTTGAATACAAAGGACGGACATCAGTGATTC 2193 CGTGAGGGTAGATGTTA T ATGGTCTGCTTGCTTGATTCTTAAA TATAATCTGAAAGTATAAGCGAGATCTAAGATCAA CAGACCAT A TAACATCT 2194 AGATGTTA T ATGGTCTG 2195 Haemophilia A TTTGATCTTAGATCTCGCTTATACTTTCAGATTATATTTAAGAA 2196 Tyr473His TCAAGCAAGCAGACCA T ATAACATCTACCCTCACGGAATCACT aTAT-CAT GATGTCCGTCCTTTGTATTCAAGGAGATTACCAA TTGGTAATCTCCTTGAATACAAAGGACGGACATCAGTGATTCC 2197 GTGAGGGTAGATGTTAT A TGGTCTGCTTGCTTGATTCTTAAAT ATAATCTGAAAGTATAAGCGAGATCTAAGATCAAA GCAGACCATATAACATC 2198 GATGTTAT A TGGTCTGC 2199 Haemophilia A TTAGATCTCGCTTATACTTTCAGATTATATTTAAGAATCAAGCA 2200 Ile475Thr AGCAGACCATATAACA T CTACCCTCACGGAATCACTGATGTCC ATC-ACC GTCCTTTGTATTCAAGGAGATTACCAAAAGGTAA TTACCTTTTGGTAATCTCCTTGAATACAAAGGACGGACATCAG 2201 TGATTCCGTGAGGGTAG A TGTTATATGGTCTGCTTGCTTGATT CTTAAATATAATCTGAAAGTATAAGCGAGATCTAA ATATAACA T CTACCCTC 2202 GAGGGTAG A TGTTATAT 2203 Haemophilia A TTATACTTTCAGATTATATTTAAGAATCAAGCAAGCAGACCATA 2204 Gly419Arg TAACATCTACCCTCAC G GAATCACTGATGTCCGTCCTTTGTAT cGGA-AGA TCAAGGAGATTACCAAAAGGTAAATATTCCCTCG CGAGGGAATATTTACCTTTTGGTAATCTCCTTGAATACAAAGG 2205 ACGGACATCAGTGATTC C GTGAGGGTAGATGTTATATGGTCT GCTTGCTTGATTCTTAAATATAATCTGAAAGTATAA ACCCTCAC G GAATCACT 2206 AGTGATTC C GTGAGGGT 2207 Haemophilia A CCAATTCTGCCAGGAGAAATATTCAAATATAAATGGACAGTGA 2208 Thr522Ser CTGTAGAAGATGGGCCA A CTAAATCAGATCCTCGGTGCCTGA aACT-TCT CCCGCTATTACTCTAGTTTCGTTAATATGGAGAGAG CTCTCTCCATATTAACGAAACTAGAGTAATAGCGGGTCAGGC 2209 ACCGAGGATCTGATTTAG T TGGCCCATCTTCTACAGTCACTGT CCATTTATATTTGAATATTTCTCCTGGCAGAATTGG ATGGGCCA A CTAAATCA 2210 TGATTTAG T TGGCCCAT 2211 Haemophilia A CCAGGAGAAATATTCAAATATAAATGGACAGTGACTGTAGAAG 2212 Asp525Asn ATGGGCCAACTAAATCA G ATCCTCGGTGCCTGACCCGCTATT aGAT-AAT ACTCTAGTTTCGTTAATATGGAGAGAGATCTAGCTT AAGCTAGATCTCTCTCCATATTAACGAAACTAGAGTAATAGCG 2213 GGTCAGGCACCGAGGAT C TGATTTAGTTGGCCCATCTTCTAC AGTCACTGTCCATTTATATTTGAATATTTCTCCTGG CTAAATCA G ATCCTCGG 2214 CCGAGGAT C TGATTTAG 2215 Haemophilia A GAAATATTCAAATATAAATGGACAGTGACTGTAGAAGATGGGC 2216 Arg527Trp CAACTAAATCAGATCCT C GGTGCCTGACCCGCTATTACTCTA tCGG-TGG GTTTCGTTAATATGGAGAGAGATCTAGCTTCAGGAC GTCCTGAAGCTAGATCTCTCTCCATATTAACGAAACTAGAGTA 2217 ATAGCGGGTCAGGCACC G AGGATCTGATTTAGTTGGCCCATC TTCTACAGTCACTGTCCATTTATATTTGAATATTTC CAGATCCT C GGTGCCTG 2218 CAGGCACC G AGGATCTG 2219 Haemophilia A TATAAATGGACAGTGACTGTAGAAGATGGGCCAACTAAATCA 2220 Arg531Cys GATCCTCGGTGCCTGACC C GCTATTACTCTAGTTTCGTTAATA cCGC-TGC TGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTC GAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAA 2221 CGAAACTAGAGTAATAGC G GGTCAGGCACCGAGGATCTGATT TAGTTGGCCCATCTTCTACAGTCACTGTCCATTTATA GCCTGACC C GCTATTAC 2222 GTAATAGC G GGTCAGGC 2223 Haemophilia A TATAAATGGACAGTGACTGTAGAAGATGGGCCAACTAAATCA 2224 Arg531Gly GATCCTCGGTGCCTGACC C GCTATTACTCTAGTTTCGTTAATA cCGC-GGC TGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTC GAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAA 2225 CGAAACTAGAGTAATAGC G GGTCAGGCACCGAGGATCTGATT TAGTTGGCCCATCTTCTACAGTCACTGTCCATTTATA GCCTGACC C GCTATTAC 2226 GTAATAGC G GGTCAGGC 2227 Haemophilia A ATAAATGGACAGTGACTGTAGAAGATGGGCCAACTAAATCAG 2228 Arg531His ATCCTCGGTGCCTGACCC G CTATTACTCTAGTTTCGTTAATAT CGC-CAC GGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCT AGAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAA 2229 CGAAACTAGAGTAATAG C GGGTCAGGCACCGAGGATCTGATT TAGTTGGCCCATCTTCTACAGTCACTGTCCATTTAT CCTGACCC G CTATTACT 2230 AGTAATAG C GGGTCAGG 2231 Haemophilia A ACAGTGACTGTAGAAGATGGGCCAACTAAATCAGATCCTCGG 2232 Ser534Pro TGCCTGACCCGCTATTAC T CTAGTTTCGTTAATATGGAGAGAG cTCT-CCT ATCTAGCTTCAGGACTCATTGGCCCTCTCCTCATCT AGATGAGGAGAGGGCCAATGAGTCCTGAAGCTAGATCTCTCT 2233 CCATATTAACGAAACTAG A GTAATAGCGGGTCAGGCACCGAG GATCTGATTTAGTTGGCCCATCTTCTACAGTCACTGT GCTATTAC T CTAGTTTC 2234 GAAACTAG A GTAATAGC 2235 Haemophilia A GTGACTGTAGAAGATGGGCCAACTAAATCAGATCCTCGGTGC 2236 Ser535Gly CTGACCCGCTATTACTCT A GTTTCGTTAATATGGAGAGAGATC tAGT-GGT TAGCTTCAGGACTCATTGGCCCTCTCCTCATCTGCT AGCAGATGAGGAGAGGGCCAATGAGTCCTGAAGCTAGATCTC 2237 TCTCCATATTAACGAAAC T AGAGTAATAGCGGGTCAGGCACC GAGGATCTGATTTAGTTGGCCCATCTTCTACAGTCAC ATTACTCT A GTTTCGTT 2238 AACGAAAC T AGAGTAAT 2239 Haemophilia A TAGAAGATGGGCCAACTAAATCAGATCCTCGGTGCCTGACCC 2240 Val537Asp GCTATTACTCTAGTTTCG T TAATATGGAGAGAGATCTAGCTTC GTT-GAT AGGACTCATTGGCCCTCTCCTCATCTGCTACAAAGA TCTTTGTAGCAGATGAGGAGAGGGCCAATGAGTCCTGAAGCT 2241 AGATCTCTCTCCATATTA A CGAAACTAGAGTAATAGCGGGTCA GGCACCGAGGATCTGATTTAGTTGGCCCATCTTCTA TAGTTTCG T TAATATGG 2242 CCATATTA A CGAAACTA 2243 Haemophilia A CAACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTA 2244 Arg541Thr GTTTCGTTAATATGGAGA G AGATCTAGCTTCAGGACTCATTGG AGA-ACA CCCTCTCCTCATCTGCTACAAAGAATCTGTAGATCA TGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCAATG 2245 AGTCCTGAAGCTAGATCT C TCTCCATATTAACGAAACTAGAGT AATAGCGGGTCAGGCACCGAGGATCTGATTTAGTTG TATGGAGA G AGATCTAG 2246 CTAGATCT C TCTCCATA 2247 Haemophilia A CTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTTT 2248 Asp542Gly CGTTAATATGGAGAGAG A TCTAGCTTCAGGACTCATTGGCCC GAT-GGT TCTCCTCATCTGCTACAAAGAATCTGTAGATCAAAG CTTTGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCA 2249 ATGAGTCCTGAAGCTAGA T CTCTCTCCATATTAACGAAACTAG AGTAATAGCGGGTCAGGCACCGAGGATCTGATTTAG GGAGAGAG A TCTAGCTT 2250 AAGCTAGA T CTCTCTCC 2251 Haemophilia A ACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTT 2252 AspS42His TCGTTAATATGGAGAGA G ATCTAGCTTCAGGACTCATTGGCC aGAT-CAT CTCTCCTCATCTGCTACAAAGAATCTGTAGATCAAA TTTGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCAAT 2253 GAGTCCTGAAGCTAGAT C TCTCTCCATATTAACGAAACTAGAG TAATAGCGGGTCAGGCACCGAGGATCTGATTTAGT TGGAGAGA G ATCTAGCT 2254 AGCTAGAT C TCTCTCCA 2255 Haemophilia A ACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTT 2256 Asp542Tyr TCGTTAATATGGAGAGA G ATCTAGCTTCAGGACTCATTGGCC aGAT-TAT CTCTCCTCATCTGCTACAAAGAATCTGTAGATCAAA TTTGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCAAT 2257 GAGTCCTGAAGCTAGAT C TCTCTCCATATTAACGAAACTAGAG TAATAGCGGGTCAGGCACCGAGGATCTGATTTAGT TGGAGAGA G ATCTAGCT 2258 AGCTAGAT C TCTCTCCA 2259 Haemophilia A GTTAATATGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCT 2260 Glu557Term CTCCTCATCTGCTACAAA G AATCTGTAGATCAAAGAGGAAACC aGAA-TAA AGGTGAGTTCTTGCCTTTCCAAGTGCTGGGTTTCAT ATGAAACCCAGCACTTGGAAAGGCAAGAACTCACCTGGTTTC 2261 CTCTTTGATCTACAGATT C TTTGTAGCAGATGAGGAGAGGGC CAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAAC GCTACAAA G AATCTGTA 2262 TACAGATT C TTTGTAGC 2263 Haemophilia A ATATGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCTCC 2264 Ser558Phe TCATCTGCTACAAAGAAT C TGTAGATCAAAGAGGAAACCAGGT TCT-TTT CAGTTCTTGCCTTTCCAAGTGCTGGGTTTCATTCTC GAGAATGAAACCCAGCACTTGGAAAGGCAAGAACTCACCTGG 2265 TTTCCTCTTTGATCTACA G ATTCTTTGTAGCAGATGAGGAGAG GGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATAT CAAAGAAT C TGTAGATC 2266 GATCTACA G ATTCTTTG 2267 Haemophilia A TGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCTCCTCA 2268 Val559Ala TCTGCTACAAAGAATCTG T AGATCAAAGAGGAAACCAGGTGA GTA-GCA GTTCTTGCCTTTCCAAGTGCTGGGTTTCATTCTCAGT ACTGAGAATGAAACCCAGCACTTGGAAAGGCAAGAACTCACC 2269 TGGTTTCCTCTTTGATCT A CAGATTCTTTGTAGCAGATGAGGA GAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCA AGAATCTG T AGATCAAA 2270 TTTGATCT A CAGATTCT 2271

EXAMPLE 14 Hemophilia—Factor IX Deficiency

The attached table discloses the correcting oligonucleotide base sequences for the Factor IX oligonucleotides of the invention.

TABLE 21 Factor IX Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Haemophilia B ATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAA 2272 Asn2Asp TCGGCCAAAGAGGTAT A ATTCAGGTAAATTGGAAGAGTTTGTT tAAT-GAT CAAGGGAACCTTGAGAGAGAATGTATGGAAGAAA TTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCT 2273 TCCAATTTACCTGAAT T ATACCTCTTTGGCCGATTCAGAATTTT GTTGGCGTTTTCATGATCAAGAAAAACTGAAAT AGAGGTAT A ATTCAGGT 2274 ACCTGAAT T ATACCTCT 2275 Haemophilia B TTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAAT 2276 Asn2lle CGGCCAAAGAGGTATA A TTCAGGTAAATTGGAAGAGTTTGTT AAT-ATT CAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAA TTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTC 2277 TTCCAATTTACCTGAA T TATACCTCTTTGGCCGATTCAGAATTT TGTTGGCGTTTTCATGATCAAGAAAAACTGAAA GAGGTATA A TTCAGGTA 2278 TACCTGAA T TATACCTC 2279 Haemophilia B ATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAA 2280 Asn2Tyr TCGGCCAAAGAGGTAT A ATTCAGGTAAATTGGAAGAGTTTGTT tAAT-TAT CAAGGGAACCTTGAGAGAGAATGTATGGAAGAAA TTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCT 2281 TCCAATTTACCTGAAT T ATACCTCTTTGGCCGATTCAGAATTTT GTTGGCGTTTTCATGATCAAGAAAAACTGAAAT AGAGGTAT A ATTCAGGT 2282 ACCTGAAT T ATACCTCT 2283 Haemophilia B TCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATC 2284 Ser3Pro GGCCAAAGAGGTATAAT T CAGGTAAATTGGAAGAGTTTGTTCA tTCA-CCA AGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT ACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAAC 2285 TCTTCCAATTTACCTG A ATTATACCTCTTTGGCCGATTCAGAA TTTTGTTGGCGTTTTCATGATCAAGAAAAACTGA GGTATAAT T CAGGTAAA 2286 TTTACCTG A ATTATACC 2287 Haemophilia B TTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGCC 2288 Gly4Asp AAAGAGGTATAATTCAG G TAAATTGGAAGAGTTTGTTCAAGGG GGT-GAT AACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAG CTACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAAC 2289 AAACTCTTCCAATTTA C CTGAATTATACCTCTTTGGCCGATTCA GAATTTTGTTGGCGTTTTCATGATCAAGAAAAA TAATTCAG G TAAATTGG 2290 CCAATTTA C CTGAATTA 2291 Haemophilia B GTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGC 2292 Gly4Ser CAAAGAGGTATAATTCA G GTAAATTGGAAGAGTTTGTTCAAGG aGGT-AGT GAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTA TACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACA 2293 AACTCTTCCAATTTAC C TGAATTATACCTCTTTGGCCGATTCA GAATTTTGTTGGCGTTTTCATGATCAAGAAAAAC ATAATTCA G GTAAATTG 2294 CAATTTAC C TGAATTAT 2295 Haemophilia B TTTCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGCCAA 2296 Lys5Glu AGAGGTATAATTCAGGT A AATTGGAAGAGTTTGTTCAAGGGAA tAAA-GAA CCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTT AACTACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGA 2297 ACAAACTCTTCCAATT T ACCTGAATTATACCTCTTTGGCCGATT CAGAATTTTGTTGGCGTTTTCATGATCAAGAAA ATTCAGGT A AATTGGAA 2298 TTCCAATT T ACCTGAAT 2299 Haemophilia B ATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTA 2300 Glu7Ala TAATTCAGGTAAATTGG A AGAGTTTGTTCAAGGGAACCTTGAG GAA-GCA AGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGA TCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTT 2301 CCCTTGAACAAACTCT T CCAATTTACCTGAATTATACCTCTTTG GCCGATTCAGAATTTTGTTGGCGTTTTCATGAT TAAATTGG A AGAGTTTG 2302 CAAACTCT T CCAATTTA 2303 Haemophilia B GATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGG 2304 Glu7Lys TATAATTCAGGTAAATTG G AAGAGTTTGTTCAAGGGAACCTTG gGAA-AAA AGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAG CTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTTC 2305 CCTTGAACAAACTCTT C CAATTTACCTGAATTATACCTCTTTGG CCGATTCAGAATTTTGTTGGCGTTTTCATGATC GTAAATTG G AAGAGTTT 2306 AAACTCTT C CAATTTAC 2307 Haemophilia B ATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTA 2308 Glu7Val TAATTCAGGTAAATTGG A AGAGTTTGTTCAAGGGAACCTTGAG GAA-GTA AGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGA TCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTT 2309 CCCTTGAACAAACTCT T CCAATTTACCTGAATTATACCTCTTTG GCCGATTCAGAATTTTGTTGGCGTTTTCATGAT TAAATTGG A AGAGTTTG 2310 CAAACTCT T CCAATTTA 2311 Haemophilia B ATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAA 2312 Glu8Ala TTCAGGTAAATTGGAAG A GTTTGTTCAAGGGAACCTTGAGAG GAG-GCG AGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGC GCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAG 2313 GTTCCCTTGAACAAAC T CTTCCAATTTACCTGAATTATACCTCT TTGGCCGATTCAGAATTTTGTTGGCGTTTTCAT ATTGGAAG A GTTTGTTC 2314 GAACAAAC T CTTCCAAT 2315 Haemophilia B ATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAA 2316 Glu8Gly TTCAGGTAAATTGGAAG A GTTTGTTCAAGGGAACCTTGAGAG GAG-GGG AGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGC GCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAG 2317 GTTCCCTTGAACAAAC T CTTCCAATTTACCTGAATTATACCTCT TTGGCCGATTCAGAATTTTGTTGGCGTTTTCAT ATTGGAAG A GTTTGTTC 2318 GAACAAAC T CTTCCAAT 2319 Haemophilia B AAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAATTC 2320 Phe9Cys AGGTAAATTGGAAGAGT T TGTTCAAGGGAACCTTGAGAGAGA TTT-TGT ATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCACG CGTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTC 2321 AAGGTTCCCTTGAACA A ACTCTTCCAATTTACCTGAATTATAC CTCTTTGGCCGATTCAGAATTTTGTTGGCGTTTT GGAAGAGT T TGTTCAAG 2322 CTTGAACA A ACTCTTCC 2323 Haemophilia B GAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAATT 2324 Phe9lle CAGGTAAATTGGAAGAG T TTGTTCAAGGGAACCTTGAGAGAG gTTT-ATT AATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCAC GTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCA 2325 AGGTTCCCTTGAACAA A CTCTTCCAATTTACCTGAATTATACC TCTTTGGCCGATTCAGAATTTTGTTGGCGTTTTC TGGAAGAG T TTGTTCAA 2326 TTGAACAA A CTCTTCCA 2327 Haemophilia B TTACATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTC 2328 Arg(-1)Ser TGAATCGGCCAAAGAG G TATAATTCAGGTAAATTGGAAGAGTT AGGt-AGC TGTTCAAGGGAACCTTGAGAGAGAATGTATGGAA TTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCC 2329 AATTTACCTGAATTATA C CTCTTTGGCCGATTCAGAATTTTGTT GGCGTTTTCATGATCAAGAAAAACTGAAATGTAA CCAAAGAG G TATAATTC 2330 GAATTATA C CTCTTTGG 2331 Haemophilia B TTTACATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATT 2332 Arg(-1)Thr CTGAATCGGCCAAAGA G GTATAATTCAGGTAAATTGGAAGAG AGG-ACG TTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGA TCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCA 2333 ATTTACCTGAATTATAC C TCTTTGGCCGATTCAGAATTTTGTTG GCGTTTTCATGATCAAGAAAAACTGAAATGTAAA GCCAAAGA G GTATAATT 2334 AATTATAC C TCTTTGGC 2335 Haemophilia B CTTTTACATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAA 2336 Lys(-2)Asn TTCTGAATCGGCCAAA G AGGTATAATTCAGGTAAATTGGAAGA AAGa-AAT GTTTGTTCAAGGGAACCTTGAGAGAGAATGTATG CATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAAT 2337 TTACCTGAATTATACCT C TTTGGCCGATTCAGAATTTTGTTGG CGTTTTCATGATCAAGAAAAACTGAAATGTAAAAG CGGCCAAA G AGGTATAA 2338 TTATACCT C TTTGGCCG 2339 Haemophilia B AATTATTCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGCC 2340 Arg(-4)Gln AACAAAATTCTGAATC G GCCAAAGAGGTATAATTCAGGTAAAT CGG-CAG TGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGA TCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTG 2341 AATTATACCTCTTTGGC C GATTCAGAATTTTGTTGGCGTTTTCA TGATCAAGAAAAACTGAAATGTAAAAGAATAATT TCTGAATC G GCCAAAGA 2342 TCTTTGGC C GATTCAGA 2343 Haemophilia B AATTATTCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGCC 2344 Arg(-4)Leu AACAAAATTCTGAATC G GCCAAAGAGGTATAATTCAGGTAAAT CGG-CTG TGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGA TCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTG 2345 AATTATACCTCTTTGGC C GATTCAGAATTTTGTTGGCGTTTTCA TGATCAAGAAAAACTGAAATGTAAAAGAATAATT TCTGAATC G GCCAAAGA 2346 TCTTTGGC C GATTCAGA 2347 Haemophilia B GAATTATTCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGC 2348 Arg(-4)Trp CAACAAAATTCTGAAT C GGCCAAAGAGGTATAATTCAGGTAAA tCGG-TGG TTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAG CTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTGA 2349 ATTATACCTCTTTGGCC G ATTCAGAATTTTGTTGGCGTTTTCAT GATCAAGAAAAACTGAAATGTAAAAGAATAATTC TTCTGAAT C GGCCAAAG 2350 CTTTGGCC G ATTCAGAA 2351 Haemophilia B GCCAACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTA 2352 Gln11Term AATTGGAAGAGTTTGTT C AAGGGAACCTTGAGAGAGAATGTAT tCAA-TAA GGAAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAG CTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCT 2353 CTCTCAAGGTTCCCTT G AACAAACTCTTCCAATTTACCTGAAT TATACCTCTTTGGCCGATTCAGAATTTTGTTGGC AGTTTGTT C AAGGGAAC 2354 GTTCCCTT G AACAAACT 2355 Haemophilia B ACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAATT 2356 Gly12Ala GGAAGAGTTTGTTCAAG G GAACCTTGAGAGAGAATGTATGGA GGG-GCG AGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTT AAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACA 2357 TTCTCTCTCAAGGTTC C CTTGAACAAACTCTTCCAATTTACCT GAATTATACCTCTTTGGCCGATTCAGAATTTTGT TGTTCAAG G GAACCTTG 2358 CAAGGTTC C CTTGAACA 2359 Haemophilia B AACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAAT 2360 Gly12Arg TGGAAGAGTTTGTTCAA G GGAACCTTGAGAGAGAATGTATGG aGGG-AGG AAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTT AAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACAT 2361 TCTCTCTCAAGGTTCC C TTGAACAAACTCTTCCAATTTACCTG AATTATACCTCTTTGGCCGATTCAGAATTTTGTT TTGTTCAA G GGAACCTT 2362 AAGGTTCC C TTGAACAA 2363 Haemophilia B ACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAATT 2364 Gly12Glu GGAAGAGTTTGTTCAAG G GAACCTTGAGAGAGAATGTATGGA GGG-GAG AGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTT AAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACA 2365 TTCTCTCTCAAGGTTC C CTTGAACAAACTCTTCCAATTTACCT GAATTATACCTCTTTGGCCGATTCAGAATTTTGT TGTTCAAG G GAACCTTG 2366 CAAGGTTC C CTTGAACA 2367 Haemophilia B CGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTC 2368 Glu17Gln AAGGGAACCTTGAGAGA G AATGTATGGAAGAAAAGTGTAGTT aGAA-CAA TTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAA TTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACAC 2369 TTTTCTTCCATACATT C TCTCTCAAGGTTCCCTTGAACAAACTC TTCCAATTTACCTGAATTATACCTCTTTGGCCG TTGAGAGA G AATGTATG 2370 CATACATT C TCTCTCAA 2371 Haemophilia B CGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTC 2372 Glu17Lys AAGGGAACCTTGAGAGA G AATGTATGGAAGAAAAGTGTAGTT aGAA-AAA TTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAA TTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACAC 2373 TTTTCTTCCATACATT C TCTCTCAAGGTTCCCTTGAACAAACTC TTCCAATTTACCTGAATTATACCTCTTTGGCCG TTGAGAGA G AATGTATG 2374 CATACATT C TCTCTCAA 2375 Haemophilia B CCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAG 2376 Cys18Arg GGAACCTTGAGAGAGAA T GTATGGAAGAAAAGTGTAGTTTTG aTGT-CGT AAGAAGCACGAGAAGTTTTTGAAAACACTGAAAGAA TTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTA 2377 CACTTTTCTTCCATAC A TTCTCTCTCAAGGTTCCCTTGAACAA ACTCTTCCAATTTACCTGAATTATACCTCTTTGG AGAGAGAA T GTATGGAA 2378 TTCCATAC A TTCTCTCT 2379 Haemophilia B CAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGG 2380 Cys18Tyr GAACCTTGAGAGAGAAT G TATGGAAGAAAAGTGTAGTTTTGAA TGT-TAT GAAGCACGAGAAGTTTTTGAAAACACTGAAAGAAC GTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACT 2381 ACACTTTTCTTCCATA C ATTCTCTCTCAAGGTTCCCTTGAACAA ACTCTTCCAATTTACCTGAATTATACCTCTTTG GAGAGAAT G TATGGAAG 2382 CTTCCATA C ATTCTCTC 2383 Haemophilia B GGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCT 2384 Glu20Val TGAGAGAGAATGTATGG A AGAAAAGTGTAGTTTTGAAGAAGC GAA-GTA ACGAGAAGTTTTTGAAAACACTGAAAGAACAGTGAG CTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTC 2385 AAAACTACACTTTTCT T CCATACATTCTCTCTCAAGGTTCCCTT GAACAAACTCTTCCAATTTACCTGAATTATACC ATGTATGG A AGAAAAGT 2386 ACTTTTCT T CCATACAT 2387 Haemophilia B TATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTG 2388 Glu21Lys AGAGAGAATGTATGGAA G AAAAGTGTAGTTTTGAAGAAGCAC aGAA-AAA GAGAAGTTTTTGAAAACACTGAAAGAACAGTGAGTA TACTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCT 2389 TCAAAACTACACTTTT C TTCCATACATTCTCTCTCAAGGTTCCC TTGAACAAACTCTTCCAATTTACCTGAATTATA GTATGGAA G AAAAGTGT 2390 ACACTTTT C TTCCATAC 2391 Haemophilia B TCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGA 2392 Cys23Arg GAATGTATGGAAGAAAAG T GTAGTTTTGAAGAAGCACGAGAA gTGT-CGT GTTTTTGAAAACACTGAAAGAACAGTGAGTATTTCCA TGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTCGT 2393 GCTTCTTCAAAACTAC A CTTTTCTTCCATACATTCTCTCTCAAG GTTCCCTTGAACAAACTCTTCCAATTTACCTGA AAGAAAAG T GTAGTTTT 2394 AAAACTAC A CTTTTCTT 2395 Haemophilia B CAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAG 2396 Cys23Tyr AATGTATGGAAGAAAAGT G TAGTTTTGAAGAAGCACGAGAAGT TGT-TAT TTTTGAAAACACTGAAAGAACAGTGAGTATTTCCAC GTGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTC 2397 GTGCTTCTTCAAAACTA C ACTTTTCTTCCATACATTCTCTCTCA AGGTTCCCTTGAACAAACTCTTCCAATTTACCTG AGAAAAGT G TAGTTTTG 2398 CAAAACTA C ACTTTTCT 2399 Haemophilia B AATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTAT 2400 Phe25Ser GGAAGAAAAGTGTAGTT T TGAAGAAGCACGAGAAGTTTTTGAA TTT-TCT AACACTGAAAGAACAGTGAGTATTTCCACATAATA TATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAAAC 2401 TTCTCGTGCTTCTTCA A AACTACACTTTTCTTCCATACATTCTC TCTCAAGGTTCCCTTGAACAAACTCTTCCAATT GTGTAGTT T TGAAGAAG 2402 CTTCTTCA A AACTACAC 2403 Haemophilia B TTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATG 2404 Glu26Gln GAAGAAAAGTGTAGTTTT G AAGAAGCACGAGAAGTTTTTGAAA tGAA-CAA ACACTGAAAGAACAGTGAGTATTTCCACATAATACC GGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAA 2405 ACTTCTCGTGCTTCTT C AAAACTACACTTTTCTTCCATACATTC TCTCTCAAGGTTCCCTTGAACAAACTCTTCCAA GTAGTTTT G AAGAAGCA 2406 TGCTTCTT C AAAACTAC 2407 Haemophilia B AAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAG 2408 Glu27Ala AAAAGTGTAGTTTTGAAG A AGCACGAGAAGTTTTTGAAAACAC GAA-GCA TGAAAGAACAGTGAGTATTTCCACATAATACCCTTC GAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTT 2409 CAAAAACTTCTCGTGCT T CTTCAAAACTACACTTTTCTTCCATA CATTCTCTCTCAAGGTTCCCTTGAACAAACTCTT TTTTGAAG A AGCACGAG 2410 CTCGTGCT T CTTCAAAA 2411 Haemophilia B AGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGA 2412 Glu27Asp AAAGTGTAGTTTTGAAGA A GCACGAGAAGTTTTTGAAAACACT GAAg-GAC GAAAGAACAGTGAGTATTTCCACATAATACCCTTCA TGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTT 2413 TCAAAAACTTCTCGTGC T TCTTCAAAACTACACTTTTCTTCCAT ACATTCTCTCTCAAGGTTCCCTTGAACAAACTCT TTTGAAGA A GCACGAGA 2414 TCTCGTGC T TCTTCAAA 2415 Haemophilia B GAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAA 2416 Glu27Lys GAAAAGTGTAGTTTTGAA G AAGCACGAGAAGTTTTTGAAAACA aGAA-AAA CTGAAAGAACAGTGAGTATTTCCACATAATACCCTT AAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTTC 2417 AAAAACTTCTCGTGCTT C TTCAAAACTACACTTTTCTTCCATAC ATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTC GTTTTGAA G AAGCACGA 2418 TCGTGCTT C TTCAAAAC 2419 Haemophilia B AAGAGTTTGTTCAAGGGAACTTGAGAGAGAATGTATGGAAG 2420 Glu27Val AAAAGTGTAGTTTTGAAG A AGCACGAGAAGTTTTTGAAAACAC GAA-GTA TGAAAGAACAGTGAGTATTTCCACATAATACCCTTC GAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTT 2421 CAAAAACTTCTCGTGCT T CTTCAAAACTACACTTTTCTTCCATA CATTCTCTCTCAAGGTTCCCTTGAACAAACTCTT TTTTGAAG A AGCACGAG 2422 CTCGTGCT T CTTCAAAA J 2423 Haemophilia B TTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT 2424 Arg29Gln GTAGTTTTGAAGAAGCAC G AGAAGTTTTTGAAAACACTGAAAG CGA-CAA AACAGTGAGTATTTCCACATAATACCCTTCAGATGC GCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAG 2425 TGTTTTCAAAAACTTCT C GTGCTTCTTCAAAACTACACTTTTCT TCCATACATTCTCTCTCAAGGTTCCCTTGAACAA AGAAGCAC G AGAAGTTT 2426 AAACTTCT C GTGCTTCT 2427 Haemophilia B TTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT 2428 Arg29Pro GTAGTTTTGAAGAAGCAC G AGAAGTTTTTGAAAACACTGAAAG CGA-CCA AACAGTGAGTATTTCCACATAATACCCTTCAGATGC GCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAG 2429 TGTTTTCAAAAACTTCT C GTGCTTCTTCAAAACTACACTTTTCT TCCATACATTCTCTCTCAAGGTTCCCTTGAACAA AGAAGCAC G AGAAGTTT 2430 AAACTTCT C GTGCTTCT 2431 Haemophilia B TTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT 2432 Arg29Term GTAGTTTTGAAGAAGCA C GAGAAGTTTTTGAAAACACTGAAAG aCGA-TGA AACAGTGAGTATTTCCACATAATACCCTTCAGATG CATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGT 2433 GTTTTCAAAAACTTCTC G TGCTTCTTCAAAACTACACTTTTCTT CCATACATTCTCTCTCAAGGTTCCCTTGAACAAA AAGAAGCA C GAGAAGTT 2434 AACTTCTC G TGCTTCTT 2435 Haemophilia B GTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGT 2436 Glu30Lys AGTTTTGAAGAAGCACGA G AAGTTTTTGAAAACACTGAAAGAA aGAA-AAA CAGTGAGTATTTCCACATAATACCCTTCAGATGCAG CTGCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTC 2437 AGTGTTTTCAAAAACTT C TCGTGCTTCTTCAAAACTACACTTTT CTTCCATACATTCTCTCTCAAGGTTCCCTTGAAC AAGCACGA G AAGTTTTT 2438 AAAAACTT C TCGTGCTT 2439 Haemophilia B GTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGT 2440 Glu30Term AGTTTTGAAGAAGCACGA G AAGTTTTTGAAAACACTGAAAGAA aGAA-TAA CAGTGAGTATTTCCACATAATACCCTTCAGATGCAG CTGCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTC 2441 AGTGTTTTCAAAAACTT C TCGTGCTTCTTCAAAACTACACTTTT CTTCCATACATTCTCTCTCAAGGTTCCCTTGAAC AAGCACGA G AAGTTTTT 2442 AAAAACTT C TCGTGCTT 2443 Haemophilia B CCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAA 2444 Glu33Asp GCACGAGAAGTTTTTGA A AACACTGAAAGAACAGTGAGTATTT GAAa-GAC CCACATAATACCCTTCAGATGCAGAGCATAGAATA TATTCTATGCTCTGCATCTGAAGGGTATTATGTGGAAATACTC 2445 ACTGTTCTTTCAGTGTT T TCAAAAACTTCTCGTGCTTCTTCAAA ACTACACTTTTCTTCCATACATTCTCTCTCAAGG GTTTTTGA A AACACTGA 2446 TCAGTGTT T TCAAAAAC 2447 Haemophilia B AACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAG 2448 Glu33Term AAGCACGAGAAGTTTTT G AAAACACTGAAAGAACAGTGAGTAT tGAA-TAA TTCCACATAATACCCTTCAGATGCAGAGCATAGAA TTCTATGCTCTGCATCTGAAGGGTATTATGTGGAAATACTCAC 2449 TGTTCTTTCAGTGTTTT C AAAAACTTCTCGTGCTTCTTCAAAAC TACACTTTTCTTCCATACATTCTCTCTCAAGGTT AAGTTTTT G AAAACACT 2450 AGTGTTTT C AAAAACTT 2451 Haemophilia B CAAAACACTTTAGATATTACCGTTAATTTGTCTTCTTTTATTCTT 2452 Trp42Term TATAGACTGAATTTT G GAAGCAGTATGTTGGTAAGCAATTCAT TGG-TAG TTTATCCTCTAGCTAATATATGAAACATATGAG CTCATATGTTTCATATATTAGCTAGAGGATAAAATGAATTGCTT 2453 ACCAACATACTGCTTC C AAAATTCAGTCTATAAAGAATAAAAG AAGACAAATTAACGGTAATATCTAAAGTGTTTTG TGAATTTT G GAAGCAGT 2454 ACTGCTTC C AAAATTCA 2455 Haemophilia B AAACACTTTAGATATTACCGTTAATTTGTCTTCTTTTATTCTTTA 2456 Lys43Glu TAGACTGAATTTTGG A AGCAGTATGTTGGTAAGCAATTCATTT gAAG-GAG TATCCTCTAGCTAATATATGAAACATATGAGAA TTCTCATATGTTTCATATATTAGCTAGAGGATAAAATGAATTGC 2457 TTACCAACATACTGCT T CCAAAATTCAGTCTATAAAGAATAAAA GAAGACAAATTAACGGTAATATCTAAAGTGTTT AATTTTGG A AGCAGTAT 2458 ATACTGCT T CCAAAATT 2459 Haemophilia B CACTTTAGATATTACCGTTAATTTGTCTTCTTTTATTCTTTATAG 2460 Gln44Term ACTGAATTTTGGAAG C AGTATGTTGGTAAGCAATTCATTTTATC gCAG-TAG CTCTAGCTAATATATGAAACATATGAGAATTA TAATTCTCATATGTTTCATATATTAGCTAGAGGATAAAATGAAT 2461 TGCTTACCAACATACT G CTTCCAAAATTCAGTCTATAAAGAATA AAAGAAGACAAATTAACGGTAATATCTAAAGTG TTTGGAAG C AGTATGTT 2462 AACATACT G CTTCCAAA 2463 Haemophilia B CCGGGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAAC 2464 Asp49Gly CTATCTCAAAGATGGAG A TCAGTGTGAGTCCAATCCATGTTTA GAT-GGT AATGGCGGCAGTTGCAAGGATGACATTAATTCCTA TAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAACATG 2465 GATTGGACTCACACTGA T CTCCATCTTTGAGATAGGTTAAGAA ATTGAATTGGCACGTAAACTGCTTAGAATGCCCGG AGATGGAG A TCAGTGTG 2466 CACACTGA T CTCCATCT 2467 Haemophilia B GCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATC 2468 Gln50His TCAAAGATGGAGATCA G TGTGAGTCCAATCCATGTTTAAATGG CAGt-CAC CGGCAGTTGCAAGGATGACATTAATTCCTATGAA TTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAA 2469 CATGGATTGGACTCACA C TGATCTCCATCTTTGAGATAGGTTA AGAAATTGAATTGGCACGTAAACTGCTTAGAATGC GGAGATCA G TGTGAGTC 2470 GACTCACA C TGATCTCC 2471 Haemophilia B GGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTA 2472 Gln50Pro TCTCAAAGATGGAGATC A GTGTGAGTCCAATCCATGTTTAAAT CAG-CCG GGCGGCAGTTGCAAGGATGACATTAATTCCTATGA TCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAAC 2473 ATGGATTGGACTCACAC T GATCTCCATCTTTGAGATAGGTTAA GAAATTGAATTGGCACGTAAACTGCTTAGAATGCC TGGAGATC A GTGTGAGT 2474 ACTCACAC T GATCTCCA 2475 Haemophilia B GGGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCT 2476 Gln50Term ATCTCAAAGATGGAGAT C AGTGTGAGTCCAATCCATGTTTAAA tCAG-TAG TGGCGGCAGTTGCAAGGATGACATTAATTCCTATG CATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAACA 2477 TGGATTGGACTCACACT G ATCTCCATCTTTGAGATAGGTTAAG AAATTGAATTGGCACGTAAACTGCTTAGAATGCCC ATGGAGAT C AGTGTGAG 2478 CTCACACT G ATCTCCAT 2479 Haemophilia B CATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCT 2480 Cys51Arg CAAAGATGGAGATCAG T GTGAGTCCAATCCATGTTTAAATGG gTGT-CGT CGGCAGTTGCAAGGATGACATTAATTCCTATGAAT ATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAA 2481 ACATGGATTGGACTCAC A CTGATCTCCATCTTTGAGATAGGTT AAGAAATTGAATTGGCACGTAAACTGCTTAGAATG GAGATCAG T GTGAGTCC 2482 GGACTCAC A CTGATCTC 2483 Haemophilia B CATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCT 2484 Cys51Ser CAAAGATGGAGATCAG T GTGAGTCCAATCCATGTTTAAATGG gTGT-AGT CGGCAGTTGCAAGGATGACATTAATTCCTATGAAT ATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAA 2485 ACATGGATTGGACTCAC A CTGATCTCCATCTTTGAGATAGGTT AAGAAATTGAATTGGCACGTAAACTGCTTAGAATG GAGATCAG T GTGAGTCC 2486 GGACTCAC A CTGATCTC 2487 Haemophilia B TTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCTCA 2488 Cys51Trp AAGATGGAGATCAGTG T GAGTCCAATCCATGTTTAAATGGCG TGTg-TGG GCAGTTGCAAGGATGACATTAATTCCTATGAATGT ACATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTT 2489 AAACATGGATTGGACTC A CACTGATCTCCATCTTTGAGATAGG TTAAGAAATTGAATTGGCACGTAAACTGCTTAGAA GATCAGTG T GAGTCCAA 2490 TTGGACTC A CACTGATC 2491 Haemophilia B TCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCTCAA 2492 Glu52Term AGATGGAGATCAGTGT G AGTCCAATCCATGTTTAAATGGCGG tGAG-TAG CAGTTGCAAGGATGACATTAATTCCTATGAATGTT AACATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATT 2493 TAAACATGGATTGGACT C ACACTGATCTCCATCTTTGAGATAG GTTAAGAAATTGAATTGGCACGTAAACTGCTTAGA ATCAGTGT G AGTCCAAT 2494 ATTGGACT C ACACTGAT 2495 Haemophilia B TTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAG 2496 Pro55Ala ATCAGTGTGAGTCCAAT C CATGTTTAAATGGCGGCAGTTGCA tCCA-GCA AGGATGACATTAATTCCTATGAATGTTGGTGTCCCT AGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAACT 2497 GCCGCCATTTAAACATG G ATTGGACTCACACTGATCTCCATCT TTGAGATAGGTTAAGAAATTGAATTGGCACGTAAA AGTCCAAT C CATGTTTA 2498 TAAACATG G ATTGGACT 2499 Haemophilia B TTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGA 2500 Pro55Arg TCAGTGTGAGTCCAATC C ATGTTTAAATGGCGGCAGTTGCAA CCA-CGA GGATGACATTAATTCCTATGAATGTTGGTGTCCCTT AAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAAC 2501 TGCCGCCATTTAAACAT G GATTGGACTCACACTGATCTCCATC TTTGAGATAGGTTAAGAAATTGAATTGGCACGTAA GTCCAATC C ATGTTTAA 2502 TTAAACAT G GATTGGAC 2503 Haemophilia B TTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGA 2504 Pro55Gln TCAGTGTGAGTCCAATC C ATGTTTAAATGGCGGCAGTTGCAA CCA-CAA GGATGACATTAATTCCTATGAATGTTGGTGTCCCTT AAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAAC 2505 TGCCGCCATTTAAACAT G GATTGGACTCACACTGATCTCCATC TTTGAGATAGGTTAAGAAATTGAATTGGCACGTAA GTCCAATC C ATGTTTAA 2506 TTAAACAT G GATTGGAC 2507 Haemophilia B TTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGA 2508 Pro55Leu TCAGTGTGAGTCCAATC C ATGTTTAAATGGCGGCAGTTGCAA CCA-CTA GGATGACATTAATTCCTATGAATGTTGGTGTCCCTT AAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAAC 2509 TGCCGCCATTTAAACAT G GATTGGACTCACACTGATCTCCATC TTTGAGATAGGTTAAGAAATTGAATTGGCACGTAA GTCCAATC C ATGTTTAA 2510 TTAAACAT G GATTGGAC 2511 Haemophilia B TTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAG 2512 Pro55Ser ATCAGTGTGAGTCCAAT C CATGTTTAAATGGCGGCAGTTGCA tCCA-TCA AGGATGACATTAATTCCTATGAATGTTGGTGTCCCT AGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAACT 2513 GCCGCCATTTAAACATG G ATTGGACTCACACTGATCTCCATCT TTGAGATAGGTTAAGAAATTGAATTGGCACGTAAA AGTCCAAT C CATGTTTA 2514 TAAACATG G ATTGGACT 2515 Haemophilia B ACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATC 2516 Cys56Arg AGTGTGAGTCCAATCCA T GTTTAAATGGCGGCAGTTGCAAGG aTGT-CGT ATGACATTAATTCCTATGAATGTTGGTGTCCCTTTG CAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCA 2517 ACTGCCGCCATTTAAAC A TGGATTGGACTCACACTGATCTCC ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACGT CCAATCCA T GTTTAAAT 2518 ATTTAAAC A TGGATTGG 2519 Haemophilia B ACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATC 2520 Cys56Ser AGTGTGAGTCCAATCCA T GTTTAAATGGCGGCAGTTGCAAGG aTGT-AGT ATGACATTAATTCCTATGAATGTTGGTGTCCCTTTG CAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCA 2521 ACTGCCGCCATTTAAAC A TGGATTGGACTCACACTGATCTCC ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACGT CCAATCCA T GTTTAAAT 2522 ATTTAAAC A TGGATTGG 2523 Haemophilia B CGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATCA 2524 Cys56Ser GTGTGAGTCCAATCCAT G TTTAAATGGCGGCAGTTGCAAGGA TGT-TCT TGACATTAATTCCTATGAATGTTGGTGTCCCTTTGG CCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGC 2525 AACTGCCGCCATTTAAA C ATGGATTGGACTCACACTGATCTCC ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACG CAATCCAT G TTTAAATG 2526 CATTTAAA C ATGGATTG 2527 Haemophilia B CGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATCA 2528 Cys56Tyr GTGTGAGTCCAATCCAT G TTTAAATGGCGGCAGTTGCAAGGA TGT-TAT TGACATTAATTCCTATGAATGTTGGTGTCCCTTTGG CCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGC 2529 AACTGCCGCCATTTAAA C ATGGATTGGACTCACACTGATCTCC ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACG CAATCCAT G TTTAAATG 2530 CATTTAAA C ATGGATTG 2531 Haemophilia B ATTCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAG 2532 Asn58Lys TCCAATCCATGTTTAAA T GGCGGCAGTTGCAAGGATGACATTA AATg-AAG ATTCCTATGAATGTTGGTGTCCCTTGGATTTGAA TTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTCA 2533 TCCTTGCAACTGCCGCC A TTTAAACATGGATTGGACTCACACT GATCTCCATCTTTGAGATAGGTTAAGAAATTGAAT TGTTTAAA T GGCGGCAG 2534 CTGCCGCC A TTTAAACA 2535 Haemophilia B TCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTC 2536 Gly59Asp CAATCCATGTTTAAATG G CGGCAGTTGCAAGGATGACATTAAT GGC-GAC TCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGG CCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGT 2537 CATCCTTGCAACTGCCG C CATTTAAACATGGATTGGACTCACA CTGATCTCCATCTTTGAGATAGGTTAAGAAATTGA TTTAAATG G CGGCAGTT 2538 AACTGCCG C CATTTAAA 2539 Haemophilia B TCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTC 2540 Gly59Val CAATCCATGTTTAAATG G CGGCAGTTGCAAGGATGACATTAAT GGC-GTC TCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGG CCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGT 2541 CATCCTTGCAACTGCCG C CATTTAAACATGGATTGGACTCACA CTGATCTCCATCTTTGAGATAGGTTAAGAAATTGA TTTAAATG G CGGCAGTT 2542 AACTGCCG C CATTTAAA 2543 Haemophilia B TTCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGT 2544 Gly59Ser CCAATCCATGTTTAAAT G GCGGCAGTTGCAAGGATGACATTAA tGGC-AGC TTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAG CTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTC 2545 ATCCTTGCAACTGCCGC C ATTTAAACATGGATTGGACTCACAC TGATCTCCATCTTTGAGATAGGTTAAGAAATTGAA GTTTAAAT G GCGGCAGT 2546 ACTGCCGC C ATTTAAAC 2547 Haemophilia B AATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCA 2548 Gly60Ser ATCCATGTTTAAATGGC G GCAGTTGCAAGGATGACATTAATTC cGGC-AGC CTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAA TTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAAT 2549 GTCATCCTTGCAACTGC C GCCATTTAAACATGGATTGGACTCA CACTGATCTCCATCTTTGAGATAGGTTAAGAAATT TAAATGGC G GCAGTTGC 2550 GCAACTGC C GCCATTTA 2551 Haemophilia B AATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCA 2552 Gly60Cys ATCCATGTTTAAATGGC G GCAGTTGCAAGGATGACATTAATTC cGGC-TGC CTATGAATGTTGGTGTCCCTTTGGATTGAAGGAA TTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAAT 2553 GTCATCCTTGCAACTGC C GCCATTTAAACATGGATTGGACTCA CACTGATCTCCATCTTTGAGATAGGTTAAGAAATT TAAATGGC G GCAGTTGC 2554 GCAACTGC C GCCATTTA 2555 Haemophilia B ATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAA 2556 Gly60Asp TCCATGTTTAAATGGCG G CAGTTGCAAGGATGACATTAATTCC GGC-GAC TATGAATGTTGGTGTCCCTTTGGATTTGAAGGAAA TTTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAA 2557 TGTCATCCTTGCAACTG C CGCCATTTAAACATGGATTGGACTC ACACTGATCTCCATCTTTGAGATAGGTTAAGAAAT AAATGGCG G CAGTTGCA 2558 TGCAACTG C CGCCATTT 2559 Haemophilia B AATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCA 2560 Gly60Arg ATCCATGTTTAAATGGC G GCAGTTGCAAGGATGACATTAATTC cGGC-CGC CTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAA TTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAAT 2561 GTCATCCTTGCAACTGC C GCCATTTAAACATGGATTGGACTCA CACTGATCTCCATCTTTGAGATAGGTTAAGAAATT TAAATGGC G GCAGTTGC 2562 GCAACTGC C GCCATTTA 2563 Haemophilia B TAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATG 2564 Cys62Tyr TTTAAATGGCGGCAGTT G CAAGGATGACATTAATTCCTATGAA TGC-TAC TGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTG CAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAGG 2565 AATTAATGTCATCCTTG C AACTGCCGCCATTTAAACATGGATT GGACTCACACTGATCTCCATCTTTGAGATAGGTTA CGGCAGTT G CAAGGATG 2566 CATCCTTG C AACTGCCG 2567 Haemophilia B TAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATG 2568 Cys62Ser TTTAAATGGCGGCAGTT G CAAGGATGACATTAATTCCTATGAA TGC-TCC TGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTG CAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAGG 2569 AATTAATGTCATCCTTG C AACTGCCGCCATTTAAACATGGATT GGACTCACACTGATCTCCATCTTTGAGATAGGTTA CGGCAGTT G CAAGGATG 2570 CATCCTTG C AACTGCCG 2571 Haemophilia B AACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGT 2572 Cys62Term TTAAATGGCGGCAGTTG C AAGGATGACATTAATTCCTATGAAT TGCa-TGA GTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGT ACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAG 2573 GAATTAATGTCATCCTT G CAACTGCCGCCATTTAAACATGGAT TGGACTCACACTGATCTCCATCTTTGAGATAGGTT GGCAGTTG C AAGGATGA 2574 TCATCCTT G CAACTGCC 2575 Haemophilia B TCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAAT 2576 Asp64Glu GGCGGCAGTTGCAAGGA T GACATTAATTCCTATGAATGTTGG GATg-GAG TGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTA TAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACAT 2577 TCATAGGAATTAATGTC A TCCTTGCAACTGCCGCCATTTAAAC ATGGATTGGACTCACACTGATCTCCATCTTTGAGA TGCAAGGA T GACATTAA 2578 TTAATGTCA T CCTTGCA 2579 Haemophilia B ATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAA 2580 Asp64Gly TGGCGGCAGTTGCAAGG A TGACATTAATTCCTATGAATGTTG GAT-GGT GTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATT AATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATT 2581 CATAGGAATTAATGTCA T CCTTGCAACTGCCGCCATTTAAACA TGGATTGGACTCACACTGATCTCCATCTTTGAGAT TTGCAAGG A TGACATTA 2582 TAATGTCA T CCTTGCAA 2583 Haemophilia B TATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAA 2584 Asp64Asn ATGGCGGCAGTTGCAAG G ATGACATTAATTCCTATGAATGTTG gGAT-AAT GTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAAT ATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTC 2585 ATAGGAATTAATGTCAT C CTTGCAACTGCCGCCATTTAAACAT GGATTGGACTCACACTGATCTCCATCTTTGAGATA GTTGCAAG G ATGACATT 2586 AATGTCAT C CTTGCAAC 2587 Haemophilia B AAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCG 2588 lle66Ser GCAGTTGCAAGGATGACA T TAATTCCTATGAATGTTGGTGTCC ATT-AGT CTTTGGATTTGAAGGAAAGAACTGTGAATTAGGTAA TTACCTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACC 2589 AACATTCATAGGAATTA A TGTCATCCTTGCAACTGCCGCCATT TAAACATGGATTGGACTCACACTGATCTCCATCTT GGATGACA T TAATTCCT 2590 AGGAATTA A TGTCATCC 2591 Haemophilia B AAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCG 2592 Ile66Thr GCAGTTGCAAGGATGACA T TAATTCCTATGAATGTTGGTGTCC ATT-ACT CTTTGGATTTGAAGGAAAGAACTGTGAATTAGGTAA TTACCTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACC 2593 AACATTCATAGGAATTA A TGTCATCCTTGCAACTGCCGCCATT TAAACATGGATTGGACTCACACTGATCTCCATCTT GGATGACA T TAATTCCT 2594 AGGAATTA A TGTCATCC 2595 Haemophilia B TGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAG 2596 Asn67Lys TTGCAAGGATGACATTAA T TCCTATGAATGTTGGTGTCCCTTT AATt-AAA GGATTTGAAGGAAAGAACTGTGAATTAGGTAAGTAA TTACTTACCTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGAC 2597 ACCAACATTCATAGGA A TTAATGTCATCCTTGCAACTGCCGCC ATTTAAACATGGATTGGACTCACACTGATCTCCA GACATTAA T TCCTATGA 2598 TCATAGGA A TTAATGTC 2599 Haemophilia B ATCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCA 2600 Tyr69Cys AGGATGACATTAATTCCT A TGAATGTTGGTGTCCCTTTGGATT TAT-TGT TGAAGGAAAGAACTGTGAATTAGGTAAGTAACTATT AATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAATCCAAA 2601 GGGACACCAACATTCA T AGGAATTAATGTCATCCTTGCAACTG CCGCCATTTAAACATGGATTGGACTCACACTGAT TAATTCCT A TGAATGTT 2602 AACATTCA T AGGAATTA 2603 Haemophilia B TGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGA 2604 Cys71Term CATTAATTCCTATGAATG T TGGTGTCCCTTTGGATTTGAAGGA TGTt-TGA AAGAACTGTGAATTAGGTAAGTAACTATTTTTTGAA TTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAA 2605 ATCCAAAGGGACACCA A CATTCATAGGAATTAATGTCATCCTT GCAACTGCCGCCATTTAAACATGGATTGGACTCA TATGAATG T TGGTGTCC 2606 GGACACCA A CATTCATA 2607 Haemophilia B GTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATG 2608 Cys71Ser ACATTAATTCCTATGAAT G TTGGTGTCCCTTTGGATTTGAAGG TGT-TCT AAAGAACTGTGAATTAGGTAAGTAACTATTTTTTGA TCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAA 2609 TCCAAAGGGACACCAA C ATTCATAGGAATTAATGTCATCCTTG CAACTGCCGCCATTTAAACATGGATTGGACTCAC CTATGAAT G TTGGTGTC 2610 GACACCAA C ATTCATAG 2611 Haemophilia B GTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATG 2612 Cys71Tyr ACATTAATTCCTATGAAT G TTGGTGTCCCTTTGGATTTGAAGG TGT-TAT AAAGAACTGTGAATTAGGTAAGTAACTATTTTTTGA TCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAA 2613 TCCAAAGGGACACCAA C ATTCATAGGAATTAATGTCATCCTTG CAACTGCCGCCATTTAAACATGGATTGGACTCAC CTATGAAT G TTGGTGTC 2614 GACACCAA C ATTCATAG 2615 Haemophilia B TGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGAT 2616 Cys71Ser GACATTAATTCCTATGAA T GTTGGTGTCCCTTTGGATTTGAAG aTGT-AGT GAAAGAACTGTGAATTAGGTAAGTAACTATTTTTTG CAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAAT 2617 CCAAAGGGACACCAAC A TTCATAGGAATTAATGTCATCCTTGC AACTGCCGCCATTTAAACATGGATTGGACTCACA CCTATGAA T GTTGGTGT 2618 ACACCAAC A TTCATAGG 2619 Haemophilia B GAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGAC 2620 Trp72Arg ATTAATTCCTATGAATGT T GGTGTCCCTTTGGATTTGAAGGAA tTGG-AGG AGAACTGTGAATTAGGTAAGTAACTATTTTTTGAAT ATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCA 2621 AATCCAAAGGGACACC A ACATTCATAGGAATTAATGTCATCCT TGCAACTGCCGCCATTTAAACATGGATTGGACTC ATGAATGT T GGTGTCCC 2622 GGGACACC A ACATTCAT 2623 Haemophilia B GTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACAT 2624 Trp72Term TAATTCCTATGAATGTTG G TGTCCCTTTGGATTTGAAGGAAAG TGGt-TGA AACTGTGAATTAGGTAAGTAACTATTTTTTGAATAC GTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTT 2625 CAAATCCAAAGGGACA C CAACATTCATAGGAATTAATGTCATC CTTGCAACTGCCGCCATTTAAACATGGATTGGAC GAATGTTG G TGTCCCTT 2626 AAGGGACA C CAACATTC 2627 Haemophilia B CCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAA 2628 Cys73Tyr TTCCTATGAATGTTGGT G TCCCTTTGGATTTGAAGGAAAGAAC TGT-TAT TGTGAATTAGGTAAGTAACTATTTTTTGAATACTC GAGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCC 2629 TTCAAATCCAAAGGGA C ACCAACATTCATAGGAATTAATGTCA TCCTTGCAACTGCCGCCATTTAAACATGGATTGG ATGTTGGT G TCCCTTTG 2630 CAAAGGGA C ACCAACAT 2631 Haemophilia B TCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTA 2632 Cys73Arg ATTCCTATGAATGTTGG T GTCCCTTTGGATTTGAAGGAAAGAA gTGT-CGT CTGTGAATTAGGTAAGTAACTATTTTTTGAATACT AGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCT 2633 TCAAATCCAAAGGGAC A CCAACATTCATAGGAATTAATGTCAT CCTTGCAACTGCCGCCATTTAAACATGGATTGGA AATGTTGG T GTCCCTTT 2634 AAAGGGAC A CCAACATT 2635 Haemophilia B CCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAA 2636 Cys73Phe TTCCTATGAATGTTGGT G TCCCTTTGGATTTGAAGGAAAGAAC TGT-TTT TGTGAATTAGGTAAGTAACTATTTTTTGAATACTC GAGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCC 2637 TTCAAATCCAAAGGGA C ACCAACATTCATAGGAATTAATGTCA TCCTTGCAACTGCCGCCATTTAAACATGGATTGG ATGTTGGT G TCCCTTTG 2638 CAAAGGGA C ACCAACAT 2639 Haemophilia B CAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAAT 2640 Cys73Term TCCTATGAATGTTGGTG T CCCTTTGGATTTGAAGGAAAGAACT TGTc-TGA GTGAATTAGGTAAGTAACTATTTTTTGAATACTCA TGAGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTC 2641 CTTCAAATCCAAAGGG A CACCAACATTCATAGGAATTAATGTC ATCCTTGCAACTGCCGCCATTTAAACATGGATTG TGTTGGTG T CCCTTTGG 2642 CCAAAGGG A CACCAACA 2643 Haemophilia B GTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGA 2644 Gly76Val ATGTTGGTGTCCCTTTG G ATTTGAAGGAAAGAACTGTGAATTA GGA-GTA GGTAAGTAACTATTTTTTGAATACTCATGGTTCAA TTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTCACA 2645 GTTCTTTCCTTCAAAT C CAAAGGGACACCAACATTCATAGGAA TTAATGTCATCCTTGCAACTGCCGCCATTTAAAC TCCCTTTG G ATTTGAAG 2646 CTTCAAAT C CAAAGGGA 2647 Haemophilia B TGTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATG 2648 Gly76Arg AATGTTGGTGTCCCTTT G GATTTGAAGGAAAGAACTGTGAATT tGGA-AGA AGGTAAGTAACTATTTTTTGAATACTCATGGTTCA TGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTCACAG 2649 TTCTTTCCTTCAAATC C AAAGGGACACCAACATTCATAGGAAT TAATGTCATCCTTGCAACTGCCGCCATTTAAACA GTCCCTTT G GATTTGAA 2650 TTCAAATC C AAAGGGAC 2651 Haemophilia B TAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATG 2652 Phe77Cys TTGGTGTCCCTTTGGAT T TGAAGGAAAGAACTGTGAATTAGGT TTT-TGT AAGTAACTATTTTTTGAATACTCATGGTTCAAAGT ACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTC 2653 ACAGTTCTTTCCTTCA A ATCCAAAGGGACACCAACATTCATAG GAATTAATGTCATCCTTGCAACTGCCGCCATTTA CTTTGGAT T TGAAGGAA 2654 TTCCTTCA A ATCCAAAG 2655 Haemophilia B TAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATG 2656 Phe77Ser TTGGTGTCCCTTTGGAT T TGAAGGAAAGAACTGTGAATTAGGT TTT-TCT AAGTAACTATTTTTTGAATACTCATGGTTCAAAGT ACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTC 2657 ACAGTTCTTTCCTTCA A ATCCAAAGGGACACCAACATTCATAG GAATTAATGTCATCCTTGCAACTGCCGCCATTTA CTTTGGAT T TGAAGGAA 2658 TTCCTTCA A ATCCAAAG 2659 Haemophilia B TAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATG 2660 Phe77Tyr TTGGTGTCCCTTTGGAT T TGAAGGAAAGAACTGTGAATTAGGT TTT-TAT AAGTAACTATTTTTTGAATACTCATGGTTCAAAGT ACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTC 2661 ACAGTTCTTTCCTTCA A ATCCAAAGGGACACCAACATTCATAG GAATTAATGTCATCCTTGCAACTGCCGCCATTTA CTTTGGAT T TGAAGGAA 2662 TTCCTTCA A ATCCAAAG 2663 Haemophiiia B AATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTT 2664 Glu78Lys GGTGTCCCTTTGGATTT G AAGGAAAGAACTGTGAATTAGGTAA tGAA-AAA GTAACTATTTTTTGAATACTCATGGTTCAAAGTTT AAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAAT 2665 TCACAGTTCTTTCCTT C AAATCCAAAGGGACACCAACATTCAT AGGAATTAATGTCATCCTTGCAACTGCCGCCATT TTGGATTT G AAGGAAAG 2666 CTTTCCTT C AAATCCAA 2667 Haemophilia B GCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGGT 2668 Gly79Val GTCCCTTTGGATTTGAAG G AAAGAACTGTGAATTAGGTAAGTA GGA-GTA ACTATTTTTTGAATACTCATGGTTCAAAGTTTCCCT AGGGAAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTAC 2669 CTAATTCACAGTTCTTT C CTTCAAATCCAAAGGGACACCAACA TTCATAGGAATTAATGTCATCCTTGCAACTGCCGC ATTTGAAG G AAAGAACT 2670 AGTTCTTT C CTTCAAAT 2671 Haemophilia B GGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGG 2672 Gly79Arg TGTCCCTTTGGATTTGAA G GAAAGAACTGTGAATTAGGTAAGT aGGA-AGA AACTATTTTTTGAATACTCATGGTTCAAAGTTTCCC GGGAAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACC 2673 TAATTCACAGTTCTTTC C TTCAAATCCAAAGGGACACCAACAT TCATAGGAATTAATGTCATCCTTGCAACTGCCGCC GATTTGAA G GAAAGAAC 2674 GTTCTTTC C TTCAAATC 2675 Haemophilia B GCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGGT 2676 Gly79Glu GTCCCTTTGGATTTGAAG G AAAGAACTGTGAATTAGGTAAGTA GGA-GAA ACTATTTTTTGAATACTCATGGTTCAAAGTTTCCCT AGGGAAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTAC 2677 CTAATTCACAGTTCTTT C CTTCAAATCCAAAGGGACACCAACA TTCATAGGAATTAATGTCATCCTTGCAACTGCCGC ATTTGAAG G AAAGAACT 2678 AGTTCTTT C CTTCAAAT 2679 Haemophilia B TTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTT 2680 Cys88Ser CTTTTAGATGTAACAT G TAACATTAAGAATGGCAGATGCGAGC TGT-TCT AGTTTTGTAAAAATAGTGCTGATAACAAGGTGGT ACCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATC 2681 TGCCATTCTTAATGTTA C ATGTTACATCTAAAAGAAGCAAAATA GACAGTAACAGCATCATTTAACATGCATTTCTAA TGTAACAT G TAACATTA 2682 TAATGTTA C ATGTTACA 2683 Haemophilia B TTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTT 2684 Cys88Phe CTTTTAGATGTAACAT G TAACATTAAGAATGGCAGATGCGAGC TGT-TTT AGTTTTGTAAAAATAGTGCTGATAACAAGGTGGT ACCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATC 2685 TGCCATTCTTAATGTTA C ATGTTACATCTAAAAGAAGCAAAATA GACAGTAACAGCATCATTTAACATGCATTTCTAA TGTAACAT G TAACATTA 2686 TAATGTTA C ATGTTACA 2687 Haemophilia B TTTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCT 2688 Cys88Arg TCTTTTAGATGTAACA T GTAACATTAAGAATGGCAGATGCGAG aTGT-CGT CAGTTTTGTAAAAATAGTGCTGATAACAAGGTGG CCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATCT 2689 GCCATTCTTAATGTTAC A TGTTACATCTAAAAGAAGCAAAATA GACAGTAACAGCATCATTTAACATGCATTTCTAAA ATGTAACA T GTAACATT 2690 AATGTTAC A TGTTACAT 2691 Haemophilia B TTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTT 2692 Cys88Tyr CTTTTAGATGTAACAT G TAACATTAAGAATGGCAGATGCGAGC TGT-TAT AGTTTTGTAAAAATAGTGCTGATAACAAGGTGGT ACCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATC 2693 TGCCATTCTTAATGTTA C ATGTTACATCTAAAAGAAGCAAAATA GACAGTAACAGCATCATTTAACATGCATTTCTAA TGTAACAT G TAACATTA 2694 TAATGTTA C ATGTTACA 2695 Haemophilia B ATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTA 2696 Ile90Thr GATGTAACATGTAACA T TAAGAATGGCAGATGCGAGCAGTTTT ATT-ACT GTAAAAATAGTGCTGATAACAAGGTGGTTTGCTC GAGCAAACCACCTTGTTATCAGCACTATTTTTACAAAACTGCT 2697 CGCATCTGCCATTCTTA A TGTTACATGTTACATCTAAAAGAAG CAAAATAGACAGTAACAGCATCATTTAACATGCAT ATGTAACA T TAAGAATG 2698 CATTCTTA A TGTTACAT 2699 Haemophilia B TGTTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGT 2700 Asn92His AACATGTAACATTAAG A ATGGCAGATGCGAGCAGTTTTGTAAA gAAT-CAT AATAGTGCTGATAACAAGGTGGTTTGCTCCTGTA TACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTACAAAA 2701 CTGCTCGCATCTGCCAT T CTTAATGTTACATGTTACATCTAAAA GAAGCAAAATAGACAGTAACAGCATCATTTAACA ACATTAAG A ATGGCAGA 2702 TCTGCCAT T CTTAATGT 2703 Haemophilia B TTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAA 2704 Asn92Lys CATGTAACATTAAGAA T GGCAGATGCGAGCAGTTTTGTAAAAA AATg-AAA TAGTGCTGATAACAAGGTGGTTTGCTCCTGTACT AGTACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTACAA 2705 AACTGCTCGCATCTGCC A TTCTTAATGTTACATGTTACATCTA AAAGAAGCAAAATAGACAGTAACAGCATCATTTAA ATTAAGAA T GGCAGATG 2706 CATCTGCC A TTCTTAAT 2707 Haemophilia B AAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACA 2708 Gly93Asp TGTAACATTAAGAATG G CAGATGCGAGCAGTTTTGTAAAAATA GGC-GAC GTGCTGATAACAAGGTGGTTTGCTCCTGTACTGA TCAGTACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTAC 2709 AAAACTGCTCGCATCTG C CATTCTTAATGTTACATGTTACATCT AAAAGAAGCAAAATAGACAGTAACAGCATCATTT TAAGAATG G CAGATGCG 2710 CGCATCTG C CATTCTTA 2711 Haemophilia B TAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAAC 2712 Gly93Ser ATGTAACATTAAGAAT G GCAGATGCGAGCAGTTTTGTAAAAAT tGGC-AGC AGTGCTGATAACAAGGTGGTTTGCTCCTGTACTG CAGTACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTACA 2713 AAACTGCTCGCATCTGC C ATTCTTAATGTTACATGTTACATCTA AAAGAAGCAAAATAGACAGTAACAGCATCATTTA TTAAGAAT G GCAGATGC 2714 GCATCTGC C ATTCTTAA 2715 Haemophilia B GATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTA 2716 Arg94Ser ACATTAAGAATGGCAG A TGCGAGCAGTTTTGTAAAAATAGTGC AGAt-AGT TGATAACAAGGTGGTTTGCTCCTGTACTGAGGGA TCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTATTT 2717 TTACAAAACTGCTCGCA T CTGCCATTCTTAATGTTACATGTTAC ATCTAAAAGAAGCAAAATAGACAGTAACAGCATC AATGGCAG A TGCGAGCA 2718 TGCTCGCA T CTGCCATT 2719 Haemophilia B TGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAAC 2720 Cys95Tyr ATTAAGAATGGCAGAT G CGAGCAGTTTTGTAAAAATAGTGCTG TGC-TAC ATAACAAGGTGGTTTGCTCCTGTACTGAGGGATA TATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTAT 2721 TTTTACAAAACTGCTCG C ATCTGCCATTCTTAATGTTACATGTT ACATCTAAAAGAAGCAAAATAGACAGTAACAGCA TGGCAGAT G CGAGCAGT 2722 ACTGCTCG C ATCTGCCA 2723 Haemophilia B GCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACA 2724 Cys95Trp TTAAGAATGGCAGATG C GAGCAGTTTTGTAAAAATAGTGCTGA TGCg-TGG TAACAAGGTGGTTTGCTCCTGTACTGAGGGATAT ATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTA 2725 TTTTTACAAAACTGCTC G CATCTGCCATTCTTAATGTTACATGT TACATCTAAAAGAAGCAAAATAGACAGTAACAGC GGCAGATG C GAGCAGTT 2726 AACTGCTC G CATCTGCC 2727 Haemophilia B GCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACA 2728 Cys95Term TTAAGAATGGCAGATG C GAGCAGTTTTGTAAAAATAGTGCTGA TGCg-TGA TAACAAGGTGGTTTGCTCCTGTACTGAGGGATAT ATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTA 2729 TTTTTACAAAACTGCTC G CATCTGCCATTCTTAATGTTACATGT TACATCTAAAAGAAGCAAAATAGACAGTAACAGC GGCAGATG C GAGCAGTT 2730 AACTGCTC G CATCTGCC 2731 Haemophilia B TACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACATTAAG 2732 Gln97Pro AATGGCAGATGCGAGC A GTTTTGTAAAAATAGTGCTGATAACA CAG-CCG AGGTGGTTTGCTCCTGTACTGAGGGATATCGACT AGTCGATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCA 2733 GCACTATTTTTACAAAAC T GCTCGCATCTGCCATTCTTAATGTT ACATGTTACATCTAAAAGAAGCAAAATAGACAGTA ATGCGAGC A GTTTTGTA 2734 TACAAAAC T GCTCGCAT 2735 Haemophilia B TTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACATTAA 2736 Gln97Glu GAATGGCAGATGCGAG C AGTTTTGTAAAAATAGTGCTGATAAC gCAG-GAG AAGGTGGTTTGCTCCTGTACTGAGGGATATCGAC GTCGATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAG 2737 CACTATTTTTACAAAACT G CTCGCATCTGCCATTCTTAATGTTA CATGTTACATCTAAAAGAAGCAAAATAGACAGTAA GATGCGAG C AGTTTTGT 2738 ACAAAACT G CTCGCATC 2739 Haemophilia B TCTATTTTGCTTCTTTTAGATGTAACATGTAACATTAAGAATGG 2740 Cys99Arg CAGATGCGAGCAGTTT T GTAAAAATAGTGCTGATAACAAGGTG tTGT-CGT GTTTGCTCCTGTACTGAGGGATATCGACTTGCAG CTGCAAGTCGATATCCCTCAGTACAGGAGCAAACCACCTTGT 2741 TATCAGCACTATTTTTAC A AAACTGCTCGCATCTGCCATTCTT AATGTTACATGTTACATCTAAAAGAAGCAAAATAGA AGCAGTTT T GTAAAAAT 2742 ATTTTTAC A AAACTGCT 2743 Haemophilia B CTATTTTGCTTCTTTTAGATGTAACATGTAACATTAAGAATGGC 2744 Cys99Tyr AGATGCGAGCAGTTTT G TAAAAATAGTGCTGATAACAAGGTG TGT-TAT GTTTGCTCCTGTACTGAGGGATATCGACTTGCAGA TCTGCAAGTCGATATCCCTCAGTACAGGAGCAAACCACCTTG 2745 TTATCAGCACTATTTTTA C AAAACTGCTCGCATCTGCCATTCTT AATGTTACATGTTACATCTAAAAGAAGCAAAATAG GCAGTTTT G TAAAAATA 2746 TATTTTTA C AAAACTGC 2747 Warfarin sensitivity TTTTTTGCTAAAACTAAAGAATTATTCTTTTACATTTCAGTTTTT 2748 Ala(-10)Thr CTTGATCATGAAAAC G CCAACAAAATTCTGAATCGGCCAAAGA cGCC-ACC GGTATAATTCAGGTAAATTGGAAGAGTTTGTTC GAACAAACTCTTCCAATTTACCTGAATTATACCTCTTTGGCCG 2749 ATTCAGAATTTTGTTGG C GTTTTCATGATCAAGAAAAACTGAAA TGTAAAAGAATAATTCTTTAGTTTTAGCAAAAAA ATGAAAAC G CCAACAAA 2750 TTTGTTGG C GTTTTCAT 2751 Warfarin sensitivity TTTTTGCTAAAACTAAAGAATTATTCTTTTACATTTCAGTTTTTC 2752 Ala(-10)Val TTGATCATGAAAACG C CAACAAAATTCTGAATCGGCCAAAGAG GCC-GTC GTATAATTCAGGTAAATTGGAAGAGTTTGTTCA TGAACAAACTCTTCCAATTTACCTGAATTATACCTCTTTGGCC 2753 GATTCAGAATTTTGTTG G CGTTTTCATGATCAAGAAAAACTGA AATGTAAAAGAATAATTCTTTAGTTTTAGCAAAAA TGAAAACG C CAACAAAA 2754 TTTTGTTG G CGTTTTCA 2755 Haemophilia B TGCAGCGCGTGAACATGATCATGGCAGAATCACCAGGCCTCA 2756 Gly(-26)Val TCACCATCTGCCTTTTAG G ATATCTACTCAGTGCTGAATGTAC GGA-GTA AGGTTTGTTTCCTTTTTTAAAATACATTGAGTATGC GCATACTCAATGTATTTTAAAAAAGGAAACAAACCTGTACATTC 2757 AGCACTGAGTAGATAT C CTAAAAGGCAGATGGTGATGAGGCC TGGTGATTCTGCCATGATCATGTTCACGCGCTGCA CCTTTTAG G ATATCTAC 2758 GTAGATAT C CTAAAAGG 2759 Haemophilia B TTATGCAGCGCGTGAACATGATCATGGCAGAATCACCAGGCC 2760 Leu(-27)Term TCATCACCATCTGCCTTT T AGGATATCTACTCAGTGCTGAATG TTA-TAA TACAGGTTTGTTTCCTTTTTTAAAATACATTGAGTA TACTCAATGTATTTTAAAAAAGGAAACAAACCTGTACATTCAGC 2761 ACTGAGTAGATATCCT A AAAGGCAGATGGTGATGAGGCCTGG TGATTCTGCCATGATCATGTTCACGCGCTGCATAA CTGCCTTT T AGGATATC 2762 GATATCCT A AAAGGCAG 2763 Haemophilia B TAGCAAAGGTTATGCAGCGCGTGAACATGATCATGGCAGAAT 2764 Ile(-30)Asn CACCAGGCCTCATCACCA T CTGCCTTTTAGGATATCTACTCAG ATC-AAC TGCTGAATGTACAGGTTTGTTTCCTTTTTTAAAATA TATTTTAAAAAAGGAAACAAACCTGTACATTCAGCACTGAGTA 2765 GATATCCTAAAAGGCAG A TGGTGATGAGGCCTGGTGATTCTG CCATGATCATGTTCACGCGCTGCATAACCTTTGCTA CATCACCA T CTGCCTTT 2766 AAAGGCAG A TGGTGATG 2767 Haemophilia B ACTAATCGACCTTACCACTTTCACAATCTGCTAGCAAAGGTTTA 2768 Ile(-40)Phe TGCAGCGCGTGAACATG A TCATGGCAGAATCACCAGGCCTCA gATC-TTC TCACCATCTGCCTTTTAGGATATCTACTCAGTGCTG CAGCACTGAGTAGATATCCTAAAAGGCAGATGGTGATGAGGC 2769 CTGGTGATTCTGCCATGA T CATGTTCACGCGCTGCATAACCTT TGCTAGCAGATTGTGAAAGTGGTAAGGTCGATTAGT TGAACATG A TCATGGCA 2770 TGCCATGA T CATGTTCA 2771 Haemophilia B ACTTTGGTACAACTAATCGACCTTACCACTTTCACAATCTGCT 2772 Arg(-44)His AGCAAAGGTTATGCAGC G CGTGAACATGATCATGGCAGAATC CGC-CAC ACCAGGCCTCATCACCATCTGCCTTTTAGGATATCT AGATATCCTAAAAGGCAGATGGTGATGAGGCCTGGTGATTCT 2773 GCCATGATCATGTTCACG C GCTGCATAACCTTTGCTAGCAGA TTGTGAAAGTGGTAAGGTCGATTAGTTGTACCAAAGT TATGCAGC G CGTGAACA 2774 TGTTCACG C GCTGCATA 2775

EXAMPLE 15 Alpha Thalassemia—Hemoglobin Alpha Locus 1

The thalassemia syndromes are a heterogeneous group of inherited anemias characterized by defects in the synthesis of one or more globin chain subunits. For example, beta-thalassemia discussed in Example 6, is caused by a decrease in beta-chain production relative to alpha-chain production; the converse is the case for alpha-thalassemia. The attached table discloses the correcting oligonucleotide base sequences for the hemoglobin alpha locus 1 oligonucleotides of the invention.

TABLE 22 HBA1 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Thalassaemia alpha CCCTGGCGCGCTCGCGGCCCGGCACTCTTCIGGTCCCCACA 2776 Met(−1)Val GACTCAGAGAGAACCCACC A TGGTGCTGICTCCTGCCGACA cATG-GTG AGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGC GCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTCTTG 2777 TCGGCAGGAGACAGCACCA T GGTGGGTTCTCTCTGAGTCTGT GGGGACCAGAAGAGTGCCGGGCCGCGAGCGCGCCAGGG AACCCACC A TGGTGCTG 2778 CAGCACCA T GGTGGGTT 2779 Haemoglobin variant CACAGACTCAGAGAGAACCCACCATGGTGCTGTCTCCTGCC 2780 Ala12Asp GACAAGACCAACGTCAAGG C CGCCTGGGGTAAGGTCGGCGC GCC-GAC GCACGCTGGCGAGTATGGTGCGGAGGCCCTGGAGAGGTG CACCTCTCCAGGGCCTCCGCACCATACTCGCCAGCGTGCGC 2781 GCCGACCTTACCCCAGGCG G CCTTGACGTTGGTCTTGTCGG CAGGAGACAGCACCATGGTGGGTTCTCTCTGAGTCTGTG CGTCAAGG C CGCCTGGG 2782 CCCAGGCG G CCTTGACG 2783 Haemoglobin variant AGAGAGAACCCACCATGGTGCTGTCTCCTGCCGACAAGACCA 2784 Gly15Asp ACGTCAAGGCCGCCTGGG G TAAGGTCGGCGCGCACGCTGG GGT-GAT CGAGTATGGTGCGGAGGCCCTGGAGAGGTGAGGCTCCCT AGGGAGCCTCACCTCTCCAGGGCCTCCGCACCATACTCGCC 2785 AGCGTGCGCGCCGACCTTA C CCCAGGCGGCCTTGACGTTGG TCTTGTCGGCAGGAGACAGCACCATGGTGGGTTCTCTCT CGCCTGGG G TAAGGTCG 2786 CGACCTTA C CCCAGGCG 2787 Haemoglobin variant CTGCCGACAAGACCMCGTCAAGGCCGCCTGGGGTAAGGTC 2788 Tyr24Cys GGCGCGCACGCTGGCGAGT A TGGTGCGGAGGCCCTGGAGA TAT-TGT GGTGAGGCTCCCTCCCCTGCTCCGACCCGGGCTCCTCGCC GGCGAGGAGCCCGGGTCGGAGCAGGGGAGGGAGCCTCACC 2789 TCTCCAGGGCCTCCGCACCA T ACTCGCCAGCGTGCGCGCCG ACCTTACCCCAGGCGGCCTTGACGTTGGTCTTGTCGGCAG TGGCGAGT A TGGTGCGG 2790 CCGCACCA T ACTCGCCA 2791 Haemoglobin variant GACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCAC 2792 Glu27Asp GCTGGCGAGTATGGTGCGGA G GCCCTGGAGAGGTGAGGCT GAGg-GAT CCCTCCCCTGCTCCGACCCGGGCTCCTCGCCCGCCCGGAC C GGTCCGGGCGGGCGAGGAGCCCGGGTCGGAGCAGGGGAG 2793 GGAGCCTCACCTCTCCAGGGC C TCCGCACCATACTCGCCAG CGTGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTC GGTGCGGA G GCCCTGGA 2794 TCCAGGGC C TCCGCACC 27955 Haemoglobin variant GAGCCACGGCTCTGCCCAGGTTAAGGGCCACGGCAAGAAGG 2796 Asn68Lys TGGCCGACGCGCTGACCAA C GCCGTGGCGCACGTGGACGA AACg-AAG CATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG CGCGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATG 2797 TCGTCCACGTGCGCCACGGC G TTGGTCAGCGCGTCGGCCAC CTTCTTGCCGTGGCCCTTAACCTGGGCAGAGCCGTGGCTC CTGACCAA C GCCGTGGC 2798 GCCACGGC G TTGGTCAG 2799 Haemoglobin variant AGGTTAAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGACC 2800 Asp74Gly AACGCCGTGGCGCACGTG G ACGACATGCCCAACGCGCTGTC GAC-GGC CGCCCTGAGCGACCTGCACGCGCACAAGCHCGGGTGGA TCCACCCGAAGCTTGTGCGCGTGCAGGTCGCTCAGGGCGGA 2801 CAGCGCGTTGGGCATGTCG T CCACGTGCGCCACGGCGTTGG TCAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAACCT GCACGTGG A CGACATGC 2802 GCATGTCG T CCACGTGC 2803 Haemoglobin variant CAGGTTAAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGAC 2804 Asp74His CAACGCCGTGGCGCACGTG G ACGACATGCCCAACGCGCTGT gGAC-CAC CCGCCCTGAGCGACCTGCACGCGCACAAGCTTCGGGTGG CCACCCGAAGCTTGTGCGCGTGCAGGTCGCTCAGGGCGGAC 2805 AGCGCGTTGGGCATGTCGT C CACGTGCGCCACGGCGTTGGT CAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAACCTG CGCACGTG G ACGACATG 2806 CATGTCGT C CACGTGCG 2807 Haemoglobin variant CACGGCAAGAAGGTGGCCGACGCGCTGACCAACGCCGTGG 2808 Asn78His CGCACGTGGACGACATGCCC A ACGCGCTGTCCGCCCTGAGC cAAC-CAC GACCTGCACGCGCACAAGCTTCGGGTGGACCCGGTCAACT AGTTGACCGGGTCCACCCGAAGCTTGTGCGCGTGCAGGTCG 2809 CTCAGGGCGGACAGCGCGT T GGGCATGTCGTCCACGTGCGC CACGGCGTTGGTCAGCGCGTCGGCCACCTTCTTGCCGTG ACATGCCC A ACGCGCTG 2810 CAGCGCGT T GGGCATGT 2811 Haemoglobin variant ACCAACGCCGTGGCGCACGTGGACGACATGCCCAACGCGCT 2812 His87Tyr GTCCGCCCTGAGCGACCTG C ACGCGCACAAGCTTCGGGTGG gCAC-TAC ACCCGGTCAACTTCAAGGTGAGCGGCGGGCCGGGAGCGA TCGCTCCCGGCCCGCCGCTCACCTTGAAGTTGACCGGGTCC 2813 ACCCGAAGCTTGTGCGCGT G CAGGTCGCTCAGGGCGGACAG CGCGTTGGGCATGTCGTCCACGTGCGCCACGGCGHGGT GCGACCTG C ACGCGCAC 2814 GTGCGCGT G CAGGTCGC 2815 Haemogiobin variant GGCGCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGA 2816 Lys90Asn GCGACCTGCACGCGCACAA G CTTCGGGTGGACCCGGTCAAC AAGc-AAC TTCAAGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGAG CTCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTTGAAGT 2817 TGACCGGGTCCACCCGAAG C TTGTGCGCGTGCAGGTCGCTC AGGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGCGCC GCGCACAA G CTTCGGGT 2818 ACCCGAAG C TTGTGCGC 2819 Haemoglobin variant TGGCGCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTG 2820 Lys90Thr AGCGACCTGCACGCGCACA A GCTTCGGGTGGACCCGGTCAA AAG-ACG CTTCAAGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGA TCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTTGAAGTT 2821 GACCGGGTCCACCCGAAGCT T GTGCGCGTGCAGGTCGCTCA GGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGCGCCA CGCGCACA A GCTTCGGG 2822 CCCGAAGC T TGTGCGCG 2823 Haemoglobin variant ACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGAGCGAC 2824 Arg92Gln CTGCACGCGCACAAGCTTC G GGTGGACCCGGTCAACTTCAA CGG-CAG GGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCG CGCCCCTCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTT 2825 GAAGTTGACCGGGTCCACC C GAAGCTTGTGCGCGTGCAGGT CGCTCAGGGCGGACAGCGCGTTGGGCATGTCGTCCACGT CAAGCTTC G GGTGGACC 2826 GGTCCACC C GAAGCTTG 2827 Haemoglobin variant ACGACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCAC 2828 Asp94Gly GCGCACAAGCTTCGGGTGG A CCCGGTCAACTTCAAGGTGAG GAC-GGC CGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATGG CCATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCCGCT 2829 CACCTTGAAGTTGACCGGG T CCACCCGAAGCTTGTGCGCGT GCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGTCGT TCGGGTGG A CCCGGTCA 2830 TGACCGGG T CCACCCGA 2831 Haemoglobin variant ACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG 2832 Pro95Arg CACAAGCTTCGGGTGGACC C GGTCAACTTCAAGGTGAGCGG CCG-CGG CGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATGGCGC GCGCCATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCC 2833 GCTCACCTTGAAGTTGACCGGG T CCACCCGAAGCTTGTGCG CGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGT GGTGGACC C GGTCAACT 2834 AGTTGACC G GGTCCACC 2835 Haemoglobin variant CGGCGGCTGCGGGCCTGGGCCCTCGGCCCCACTGACCCTC 2836 Ser102Arg TCTCTGCACAGCTCCTAAG C CACTGCCTGCTGGTGACCCTG AGCc-AGA GCCGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCAC GTGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGGCGGCC 2837 AGGGTCACCAGCAGGCAGTG G CTTAGGAGCTGTGCAGAGAA GAGGGTCAGTGGGGCCGAGGGCCCAGGCCCGCAGCCGCCG CTCCTAAG C CACTGCCT 2838 AGGCAGTG G CTTAGGAG 2839 Haemoglobin variant TTCTCTGCACAGCTCCTAAGCCACTGCCTGCTGGTGACCCTG 2840 Glu116Lys GCCGCCCACCTCCCCGCC G AGTTCACCCCTGCGGTGCACGC cGAG-AAG CTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTGC GCACGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCG 2841 TGCACCGCAGGGGTGAACT C GGCGGGGAGGTGGGCGGCCA GGGTCACCAGCAGGCAGTGGCTTAGGAGCTGTGCAGAGAA TCCCCGCC G AGTTCACC 2842 GGTGAACT C GGCGGGGA 2843 Haemoglobin variant TCCTAAGCCACTGCCTGCTGGTGACCCTGGCCGCCCACCTC 2844 Ala120Glu CCCGCCGAGTTCACCCCTG C GGTGCACGCCTCCCTGGACAA GCG-GAG GTTCCTGGCTTCTGTGAGCACCGTGCTGACCTCCAAATA TATTTGGAGGTCAGCACGGTGCTCACAGAAGCCAGGAACTTG 2845 TCCAGGGAGGCGTGCACC G CAGGGGTGAACTCGGCGGGGA GGTGGGCGGCCAGGGTCACCAGCAGGCAGTGGCTTAGGA CACCCCTG C GGTGCACG 2846 CGTGCACC G CAGGGGTG 2847 Thalassaemia alpha TGGCCGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCAC 2848 Leu129Pro GCCTCCCTGGACAAGTTCC T GGCTTCTGTGAGCACCGTGCTG CTG-CCG ACCTCCAAATACCGTTAAGCTGGAGCCTCGGTGGCCAT ATGGCCACCGAGGCTCCAGCHAACGGTATTTGGAGGTCAGC 2849 ACGGTGCTCACAGAAGCC A GGAACTTGTCCAGGGAGGCGTG CACCGCAGGGGTGAACTCGGCGGGGAGGTGGGCGGCCA CAAGTTCC T GGCTTCTG 2850 CAGAAGCC A GGAACTTG 2851 Haemoglobin variant TGCACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCG 2852 Arg141Leu TGCTGACCTCCAAATACC G TTAAGCTGGAGCCTCGGTGGCCA CGT-CTT TGCTTCTTGCCCCTTGGGCCTCCCCCCAGCCCCTCCT AGGAGGGGCTGGGGGGAGGCCCAAGGGGCMGMGCATGG 2853 CCACCGAGGCTCCAGCTTAA C GGTATTTGGAGGTCAGCACG GTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTGCA CMATACC G TTAAGCTG 2854 CAGCTTAA C GGTATTTG 2855

EXAMPLE 16 Alpha-thalassemia—Hemoglobin Alpha Locus 2

The attached table discloses the correcting oligonucleotide base sequences for the hemoglobin alpha locus 2 oligonucleotides of the invention.

TABLE 23 HBA2 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO Thalassaemia alpha CCTGGCGCGCTCGCGGGCCGGCACTCTTCTGGTCCCCACAG 2856 Met(-1)Thr ACTCAGAGAGAACCCACCA T GGTGCTGTCTCCTGCCGACAAG ATG-ACG ACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCA TGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTCTT 2857 GTCGGCAGGAGACAGCACC A TGGTGGGTTCTCTCTGAGTCT GTGGGGACCAGAAGAGTGCCGGCCCGCGAGCGCGCCAGG ACCCACCA T GGTGCTGT 2858 ACAGCACC A TGGTGGGT 2859 Haemoglobin variant CACAGACTCAGAGAGAACCCACCATGGTGCTGTCTCCTGCC 2860 Ala12Asp GACAAGACCAACGTCAAGG C CGCCTGGGGTAAGGTCGGCGC GCC-GAC GCACGCTGGCGAGTATGGTGCGGAGGCCCTGGAGAGGTG CACCTCTCCAGGGCCTCCGCACCATACTCGCCAGCGTGCGC 2861 GCCGACCTTACCCCAGGCG G CCTTGACGTTGGTCTTGTCGG CAGGAGACAGCACCATGGTGGGTTCTCTCTGAGTCTGTG CGTCAAGG C CGCCTGGG 2862 CCCAGGCG G CCTTGACG 2863 Haemoglobin variant AGAGAACCCACCATGGTGCTGTCTCCTGCCGACAAGACCAAC 2864 Lys16Glu GTCAAGGCCGCCTGGGGT A AGGTCGGCGCGCACGCTGGCG tAAG-GAG AGTATGGTGCGGAGGCCCTGGAGAGGTGAGGCTCCCTCC GGAGGGAGCCTCACCTCTCCAGGGCCTCCGCACCATACTCG 2865 CCAGCGTGCGCGCCGACCT T ACCCCAGGCGGCCTTGACGTT GGTCTTGTCGGCAGGAGACAGCACCATGGTGGGTTCTCT CCTGGGGT A AGGTCGGC 2866 GCCGACCT T ACCCCAGG 2867 Haemoglobin variant GGTGCTGTCTCCTGCCGACAAGACCAACGTCAAGGCCGCCT 2868 His20Gln GGGGTAAGGTCGGCGCGCA C GCTGGCGAGTATGGTGCGGA CACg-CAA GGCCCTGGAGAGGTGAGGCTCCCTCCCCTGCTCCGACCCG CGGGTCGGAGCAGGGGAGGGAGCCTCACCTCTCCAGGGCC 2869 TCCGCACCATACTCGCCAGC G TGCGCGCCGACCTTACCCCA GGCGGCCTTGACGTTGGTCTTGTCGGCAGGAGACAGCACC GGCGCGCA C GCTGGCGA 2870 TCGCCAGC G TGCGCGCC 2871 Haemoglobin variant GACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCAC 2872 Glu27Asp GCTGGCGAGTATGGTGCGGA G GCCCTGGAGAGGTGAGGCT GAGg-GAC CCCTCCCCTGCTCCGACCCGGGCTCCTCGCCCGCCCGGAC C GGTCCGGGCGGGCGAGGAGCCCGGGTCGGAGCAGGGGAG 2873 GGAGCCTCACCTCTCCAGGGC C TCCGCACCATACTCGCCAG CGTGCGCGCCGACCTTACCCCAGGCGGCCHGACGHGGTC GGTGCGGA G GCCCTGGA 2874 TCCAGGGC C TCCGCACC 2875 Thalassaemia alpha ACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCACGCTGG 2876 Leu29Pro CGAGTATGGTGCGGAGGCCC T GGAGAGGTGAGGCTCCCTCC CTG-CCG CCTGCTCCGACCCGGGCTCCTCGCCCGCCCGGACCCACAG CTGTGGGTCCGGGCGGGCGAGGAGCCCGGGTCGGAGCAGG 2877 GGAGGGAGCCTCACCTCTCC A GGGCCTCCGCACCATACTCG CCAGCGTGCGCGCCGACCTTACCCCAGGCGGCCTTGACGT GGAGGCCC T GGAGAGGT 2878 ACCTCTCC A GGGCCTCC 2879 Haemoglobin variant GCTTCTCCCCGCAGGATGTTCCTGTCCTTCCCCACCACCAAG 2880 Asp47His ACCTACTTCCCGCACTTC G ACCTGAGCCACGGCTCTGCCCA cGAC-CAC GGHAAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGA TCAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAACCTGG 2881 GCAGAGCCGTGGCTCAGGT C GAAGTGCGGGAAGTAGGTCTT GGTGGTGGGGAAGGACAGGAACATCCTGCGGGGAGAAGC CGCACTTC G ACCTGAGC 2882 GCTCAGGT C GAAGTGCG 2883 Haemoglobin variant CTCCCCGCAGGATGTTCCTGTCCTTCCCCACCACCAAGACCT 2884 Leu48Arg ACTTCCCGCACTTCGACC T GAGCCACGGCTCTGCCCAGGTTA CTG-CGG AGGGCCACGGCAAGAAGGTGGCCGACGCGCTGACCAA TTGGTCAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAAC 2885 CTGGGCAGAGCCGTGGCTC A GGTCGAAGTGCGGGAAGTAG GTCTTGGTGGTGGGGAAGGACAGGAACATCCTGCGGGGAG CTTCGACC T GAGCCACG 2886 CGTGGCTC A GGTCGAAG 2887 Haemoglobin variant CTGTCCTTCCCCACCACCAAGACCTACTTCCCGCACTTCGAC 2888 Gln54Glu CTGAGCCACGGCTCTGCC C AGGTTAAGGGCCACGGCAAGAA cCAG-GAG GGTGGCCGACGCGCTGACCAACGCCGTGGCGCACGTGG CCACGTGCGCCACGGCGTTGGTCAGCGCGTCGGCCACCHC 2889 TTGCCGTGGCCCTTAACCT G GGCAGAGCCGTGGCTCAGGTC GAAGTGCGGGAAGTAGGTCTTGGTGGTGGGGAAGGACAG GCTCTGCC C AGGTTAAG 2890 CTTAACCT G GGCAGAGC 2891 Haemoglobin variant CCAAGACCTACTTCCCGCACTTCGACCTGAGCCACGGCTCTG 2892 Gly59Asp CCCAGGTTAAGGGCCACG G CAAGAAGGTGGCCGACGCGCT GGC-GAC GACCAACGCCGTGGCGCACGTGGACGACATGCCCAACGC GCGTTGGGCATGTCGTCCACGTGCGCCACGGCGTTGGTCAG 2893 CGCGTCGGCCACCTTCTTG C CGTGGCCCTTAACCTGGGCAG AGCCGTGGCTCAGGTCGAAGTGCGGGAAGTAGGTCTTGG GGGCCACG G CAAGAAGG 2894 CCTTCTTG C CGTGGCCC 2895 Haemoglobin variant GAGCCACGGCTCTGCCCAGGTTAAGGGCCACGGCAAGAAGG 2896 Asn68Lys TGGCCGACGCGCTGACCAA C GCCGTGGCGCACGTGGACGA AACg-AAG T CATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG CGCGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATG 2897 TCGTCCACGTGCGCCACGGC G TTGGTCAGCGCGTCGGCCAC CTTCTTGCCGTGGCCCTTAACCTGGGCAGAGCCGTGGCTC CTGACCAA C GCCGTGGC 2898 GCCACGGC G TTGGTCAG 2899 Haemoglobin variant GAGCCACGGCTCTGCCCAGGTAAAGGGCCACGGCAAGAAGG 2900 Asn68Lys TGGCCGACGCGCTGACCAA C GCCGTGGCGCACGTGGACGA AACg-AAA CATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG CGCGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATG 2901 TCGTCCACGTGCGCCACGGC G TTGGTCAGCGCGTCGGCCAC CTTCTTGCCGTGGCCCTTAACCTGGGCAGAGCCGTGGCTC CTGACCAA C GCCGTGGC 2902 GCCACGGC G TTGGTCAG 2903 Haemoglobin variant CGGCAAGAAGGTGGCCGACGCGCTGACCAACGCCGTGGCG 2904 Asn78Lys CACGTGGACGACATGCCCAA C GCGCTGTCCGCCCTGAGCGA AACg-AAA CCTGCACGCGCACAAGCTTCGGGTGGACCCGGTCAACTTC GAAGTTGACCGGGTCCACCCGAAGCTTGTGCGCGTGCAGGT 2905 CGCTCAGGGCGGACAGCGC G TTGGGCATGTCGTCCACGTGC GCCACGGCGTTGGTCAGCGCGTCGGCCACCTTCTTGCCG ATGCCCAA C GCGCTGTC 2906 GACAGCGC G TTGGGCAT 2907 Haemoglobin variant CGCTGACCAACGCCGTGGCGCACGTGGACGACATGCCCAAC 2908 Asp85Val GCGCTGTCCGCCCTGAGCG A CCTGCACGCGCACAAGCTTCG GAC-GTC GGTGGACCCGGTCAACTTCAAGGTGAGCGGCGGGCCGGG CCCGGCCCGCCGCTCACCTTGAAGTTGACCGGGTCCACCCG 2909 AAGCTTGTGCGCGTGCAGG T CGCTCAGGGCGGACAGCGCGT TGGGCATGTCGTCCACGTGCGCCACGGCGTTGGTCAGCG CCTGAGCG A CCTGCACG 2910 CGTGCAGG T CGCTCAGG 2911 Haemoglobin variant GGCGCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGA 2912 Lys90Asn GCGACCTGCACGCGCACAA G CTTCGGGTGGACCCGGTCAAC AAGc-AAT TTCAAGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGAG CTCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTTGAAGT 2913 TGACCGGGTCCACCCGAAG C TTGTGCGCGTGCAGGTCGCTC AGGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGCGCC GCGCACAA G CTTCGGGT 2914 ACCCGAAG C TTGTGCGC 2915 Haemoglobin variant GACGACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCA 2916 Asp94His CGCGCACAAGCTTCGGGTG G ACCCGGTCAACTTCAAGGTGA gGAC-CAC GCGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATG CATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCCGCTC 2917 ACCTTGAAGTTGACCGGGT C CACCCGAAGCTTGTGCGCGTG CAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGTCGTC . TTCGGGTG G ACCCGGTC 2918 GACCGGGT C CACCCGAA 2919 Haemoglobin variant ACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG 2920 Pro95Leu CACAAGCTTCGGGTGGACC C GGTCAACTTCAAGGTGAGCGG CCG-CTG CGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATGGCGC GCGCCATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCC 2921 GCTCACCTTGAAGTTGACC G GGTCCACCCGAAGCTTGTGCG CGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGT GGTGGACC C GGTCAACT 2922 AGTTGACC G GGTCCACC 2923 Haemoglobin variant TAGCGCAGGCGGCGGCTGCGGGCCTGGGCCGCACTGACCC 2924 Ser102Arg TCTTCTCTGCACAGCTCCTA A GCCACTGCCTGCTGGTGACCC aAGC-CGC TGGCCGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGC GCACCGCAGGGGTGAACTCGGCGGGGAGGTGGGCGGCCAG 2925 GGTCACCAGCAGGCAGTGGC T TAGGAGCTGTGCAGAGAAGA GGGTCAGTGCGGCCCAGGCCCGCAGCCGCCGCCTGCGCTA AGCTCCTA A GCCACTGC 2926 GCAGTGGC T TAGGAGCT 2927 Haemoglobin H disease GGCGGCGGCTGCGGGCCTGGGCCGCACTGACCCTCTTCTCT 2928 Cys104Tyr GCACAGCTCCTAAGCCACT G CCTGCTGGTGACCCTGGCCGC TGC-TAC CCACCTCCCCGCCGAGTTCACCCCTGCGGTGCACGCCTC GAGGCGTGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGG 2929 CGGCCAGGGTCACCAGCAGG C AGTGGCTTAGGAGCTGTGCA GAGAAGAGGGTCAGTGCGGCCCAGGCCCGCAGCCGCCGCC AAGCCACT G CCTGCTGG 2930 CCAGCAGG C AGTGGCTT 2931 Haemoglobin variant CCGCACTGACCCTCTTCTCTGCACAGCTCCTAAGCCACTGCC 2932 Ala111Val TGCTGGTGACCCTGGCCG C CCACCTCCCCGCCGAGTTCACC GCC-GTC CCTGCGGTGCACGCCTCCCTGGACAAGTTCCTGGCTTC GAAGCCAGGAACTTGTCCAGGGAGGCGTGCACCGCAGGGGT 2933 GAACTCGGCGGGGAGGTGG G CGGCCAGGGTCACCAGCAGG CAGTGGCTTAGGAGCTGTGCAGAGAAGAGGGTCAGTGCGG CCTGGCCG C CCACCTCC 2934 GGAGGTGG G CGGCCAGG 2935 Haemoglobin variant TCCTAAGCCACTGCCTGCTGGTGACCCTGGCCGCCCACCTC 2936 Ala210Glu CCCGCCGAGTTCACCCCTG C GGTGCACGCCTCCCTGGACAA GCG-GAG GTTCCTGGCTTCTGTGAGCACCGTGCTGACCTCCAAATA TATTTGGAGGTCAGCACGGTGCTCACAGAAGCCAGGAACTTG 2937 TCCAGGGAGGCGTGCACC G CAGGGGTGAACTCGGCGGGGA GGTGGGCGGCCAGGGTCACCAGCAGGCAGTGGCTTAGGA CACCCCTG C GGTGCACG 2938 CGTGCACC G CAGGGGTG 2939 Haemoglobin variant CCACTGCCTGCTGGTGACCCTGGCCGCCCACCTCCCCGCCG 2940 His122Gln AGTTCACCCCTGCGGTGCA C GCCTCCCTGGACAAGTTCCTG CACq-CAG GCTTCTGTGAGCACCGTGCTGACCTCCAAATACCGTTAA TTAACGGTATTTGGAGGTCAGCACGGTGCTCACAGAAGCCAG 2941 GAACTTGTCCAGGGAGGC G TGCACCGCAGGGGTGAACTCGG CGGGGAGGTGGGCGGCCAGGGTCACCAGCAGGCAGTGG GCGGTGCA C GCCTCCCT 2942 AGGGAGGC G TGCACCGC 2943 Haemoglobin variant CACTGCCTGCTGGTGACCCTGGCCGCCCACCTCCCCGCCGA 2944 Ala123Ser GTTCACCCCTGCGGTGCAC G CCTCCCTGGACAAGTTCCTGG cGCC-TCC CTTCTGTGAGCACCGTGCTGACCTCCAAATACCGTTAAG CTTAACGGTATTTGGAGGTCAGCACGGTGCTCACAGAAGCCA 2945 GGAACTTGTCCAGGGAGG C GTGCACCGCAGGGGTGAACTCG GCGGGGAGGTGGGCGGCCAGGGTCACCAGCAGGCAGTG CGGTGCAC G CCTCCCTG 2946 CAGGGAGG C GTGCACCG 2947 Thalassaemia alpha TGCTGGTGACCCTGGCCGCCCACCTCCCCGCCGAGTTCACC 2948 Leu125Pro CCTGCGGTGCACGCCTCCC T GGACAAGTTCCTGGCTTCTGT CTG-CCG GAGCACCGTGCTGACCTCCAAATACCGTTAAGCTGGAGC GQTCCAGCTTAACGGTATTTGGAGGTCAGCACGGTGCTCACA 2949 GAAGCCAGGAACHGTCC A GGGAGGCGTGCACCGCAGGGG TGAACTCGGCGGGGAGGTGGGCGGCCAGGGTCACCAGCA CGCCTCCC T GGACAAGT 2950 ACTTGTCC A GGGAGGCG 2951 Haemoglobin variant GCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCACGCCTC 2952 Ser131Pro CCTGGACAAGTfCCTGGCT T CTGTGAGCACCGTGCTGACCTC tTCT-CCT CAAATACCGTTAAGCTGGAGCCTCGGTAGCCGTTCCTC GAGGAACGGCTACCGAGGCTCCAGCTTAACGGTATTTGGAG 2953 GTCAGCACGGTGCTCACAG A AGCCAGGAACTTGTCCAGGGA GGCGTGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGGC TCCTGGCT T CTGTGAGC 2954 GCTCACAG A AGCCAGGA 2955 Haemoglobin variant GAGTTCACCCCTGCGGTGCACGCCTCCCTGGACAAGTTCCT 2956 Leu136Met GGCTTCTGTGAGCACCGTG C TGACCTCCAAATACCGTTAAGC gCTG-ATG TGGAGCCTCGGTAGCCGTTCCTCCTGCCCGCTGGGCCT AGGCCCAGCGGGCAGGAGGAACGGCTACCGAGGCTCCAGC 2957 TTAACGGTATTTGGAGGTCA G CACGGTGCTCACAGAAGCCAG GAACTTGTCCAGGGAGGCGTGCACCGCAGGGGTGAACTC GCACCGTG C TGACCTCC 2958 GGAGGTCA G CACGGTGC 2959 Haemoglobin variant AGTTCACCCCTGCGGTGCACGCCTCCCTGGACAAGTTCCTG 2960 Leu136Pro GCTTCTGTGAGCACCGTGC T GACCTCCAAATACCGTTAAGCT CTG-CCG GGAGCCTCGGTAGCCGTTCCTCCTGCCCGCTGGGCCTC GAGGCCCAGCGGGCAGGAGGAACGGCTACCGAGGCTCCAG 2961 CTTAACGGTATTTGGAGGTC A GCACGGTGCTCACAGAAGCCA GGAACTTGTCCAGGGAGGCGTGCACCGCAGGGGTGAACT CACCGTGC T GACCTCCA 2962 TGGAGGTC A GCACGGTG 2963 Haemoglobin variant GTGCACGCCTCGCTGGACAAGTTCCTGGCTTCTGTGAGCACC 2964 Arg141Cys GTGCTGACCTCCAAATAC C GTTAAGCTGGAGCCTCGGTAGCC cCGT-TGT GTTCCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCC GGAGGGCCCGTTGGGAGGCCCAGCGGGGAGGAGGAACGGC 2965 TACCGAGGCTCCAGCTTAAC G GTATTTGGAGGTCAGCACGGT GCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTGCAC CCAAATAC C GTTAAGCT 2966 AGCTTAAC G GTATTTGG 2967 Haemoglobin variant CACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTG 2968 Term142Gln CTGACCTCCAAATACCGT T AAGCTGGAGCCTCGGTAGCCGTT tTAA-CAA CCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCC GGAGGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGGAAC 2969 GGCTACCGAGGCTCCAGCTT A ACGGTATTTGGAGGTCAGCA CGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTG AATACCGT T AAGCTGGA 2970 TCCAGCTT A ACGGTATT 2971 Haemoglobin variant CACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTG 2972 Term142Lys CTGACCTCCAAATACCGT T AAGCTGGAGCCTCGGTAGCCGTT tTAA-AAA CCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCC GGAGGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGGAAC 2973 GGCTACCGAGGCTCCAGCTT A ACGGTATTTGGAGGTCAGCA CGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTG AATACCGT T AAGCTGGA 2974 TCCAGCTT A ACGGTATT 2975 Haemoglobin variant CGCCTCCGTGGACAAGTTCCTGGCTTCTGTGAGCACCGTGCT 2976 Term142Tyr GACCTCCAAATACCGTTA A GCTGGAGCCTCGGTAGCCGTTCC TAAg-TAT TCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCCCC GGGGAGGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGG 2977 AACGGCTACCGAGGCTCCAGC T TAACGGTATTTGGAGGTCAG CACGGTGCTCACAGAAGCCAGGAACHGTCCAGGGAGGCG TACCGTTA A GCTGGAGC 2978 GCTCCAGC T TAACGGTA 2979

EXAMPLE 17 Human Mismatch Repair—MLH1

The human MLH1 gene is homologous to the bacterial mutL gene, which is involved in mismatch repair. Mutations in the MLH1 gene have been identified in many individuals with hereditary nonpolyposis colorectal cancer (HNPCC). Mutations in the MLH1 gene are also implicated in predisposition to a variety of cancers associated with, for example, Muir-Torre syndrome and Turcot syndrome. The attached table discloses the correcting oligonucleotide base sequences for the MLH1 oligonucleotides of the invention.

TABLE 24 MLH1 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Non-polyposis TTGGCTGAAGGCACTTCCGTTGAGCATCTAGACGTTTCCTTG 2980 colorectal cancer GCTCTTCTGGCGCCAAAA T GTCGTTCGTGGCAGGGGTTATTC Met1Arg GGCGGCTGGACGAGACAGTGGTGAACCGCATCGCGGC ATG-AGG GCCGCGATGCGGTTCACCACTGTCTCGTCCAGCCGCCGAAT 2981 AACCCCTGCCACGAACGAC A TTTTGGCGCCAGAAGAGCCAA GGAAACGTCTAGATGCTCAACGGAAGTGCCTTCAGCCAA CGCCAAAA T GTCGTTCG 2982 CGAACGAC A TTTTGGCG 2983 Non-polyposis TTGGCTGAAGGCACTTCCGTTGAGCATCTAGACGTTTCCTTG 2984 colorectal cancer GCTCTTCTGGCGCCAAAA T GTCGTTCGTGGCAGGGGTTATTC Met1Lys GGCGGCTGGACGAGACAGTGGTGAACCGCATCGCGGC ATG-AAG GCCGCGATGCGGTTCACCACTGTCTCGTCCAGCCGCCGAAT 2985 AACCCCTGCCACGAACGAC A TTTTGGCGCCAGAAGAGCCAA GGAAACGTCTAGATGCTCAACGGAAGTGCCTTCAGCCAA CGCCAAAA T GTCGTTCG 2986 CGAACGAC A TTTTGGCG 2987 Non-polyposis TGGTGAACCGCATCGCGGCGGGGGAAGTTATCCAGCGGCCA 2988 colorectal cancer GCTAATGCTATCAAAGAGA T GATTGAGAACTGGTACGGAGGG Met35Arg AGTCGAGCCGGGCTCACTTAAGGGCTACGACTTAACGG ATG-AGG CCGTTAAGTCGTAGCCCTTAAGTGAGCCCGGCTCGACTCCCT 2989 CCGTACCAGTTCTCAATC A TCTCTTTGATAGCATTAGCTGGCC GCTGGATAACTTCCCCCGCCGCGATGCGGTTCACCA CAAAGAGA T GATTGAGA 2990 TCTCAATC A TCTCTTTG 2991 Non-polyposis TAGAGTAGTTGCAGACTGATAAATTATTTTCTGTTTGATTTGCC 2992 colorectal cancer AGTTTAGATGCTAAAAT C CACAAGTATTCAAGTGATTGTTAAAG Ser44Phe AGGGAGGCCTGAAGTTGATTCAGATCCAAGACAA TCC-TTC TTGTCTTGGATCTGAATCAACTTGAGGCCTCCCTCTTTAACAA 2993 TCACTTGAATACTTGTG G ATTTTGCATCTTAAACTGGCAAATCA AACAGAAAATAATTTATCAGTCTGCAACTACTCTA TGCAAAAT C CACAAGTA 2994 TACTTGTG G ATTTTGCA 2995 Non-polyposis GCAAAATCCACAAGTATTCAAGTGATTGTTAAAGAGGGAGGC 2996 colorectal cancer CTGAAGTTGATTCAGATC C AAGACAATGGCACCGGGATCAGG Gln62Lys GTAAGTAAAACCTCAAAGTAGCAGGATGTTTGTGCGC CAA-AAA GCGCACTAAACATCCTGCTACTTTGAGGTTTTACTTACCCTGAT 2997 CCCGGTGCCATTGTCTT G GATCTGAATCAACTTCAGGCCTCC CTCTTTAACAATCACTTGAATACTTGTGGATTTTGC TTCAGATC C AAGACAAT 2998 ATTGTCTT G GATCTGAA 2999 Non-polyposis GCAAAATCCACAAGTATTCAAGTGATTGTTAAAGAGGGAGGC 3000 colorectal cancer CTGAAGTTGATTCAGATC C AAGACAATGGCACCGGGATCAGG Gln62Term GTAAGTAAAACCTCAAAGTAGCAGGATGTTTGTGCGC CAA-TAA GCGCACAAACATCCTGCTACTTTGAGGTTTTACTTACCCTGAT 3001 CCCGGTGCCATTGTCTT G GATCTGAATCAACTTCAGGCCTCC CTCTTTAACAATCACTTGAATACTTGTGGATTTTGC TTCAGATC C AAGACAAT 3002 ATTGTCTT G GATCTGAA 3003 Non-polyposis CCACAAGTATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGT 3004 colorectal cancer TGATTCAGATCCAAGACA A TGGCACCGGGATCAGGGTAAGTA Asn64Ser AAACCTCAAAGTAGCAGGATGTTTGTGCGCTTCATGG AAT-AGT CCATGAAGCGCACAAACATCCTGCTACTTTGAGGTTTTACTTA 3005 CCCTGATCCCGGTGCCA T TCTCTTGGATCTGAATCAACTTCA GGCCTCCCTCTTTAACAATCACTTGAATACTTGTGG CCAAGACA A TGGCACCG 3006 CGGTGCCA T TGTCTTGG 3007 Non-polyposis ATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGTTGATTCAGA 3008 colorectal cancer TCCAAGACAATGGCACC G GGATCAGGGTAAGTAAAAACCTCAA Gly67Arg AGTAGCAGGATGTTTGTGCGCTTCATGGAAGAGTCA GGG-AGG TGACTCTTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGT 3009 TTTACTTACCCTGATCC C GGTGCCATTGTCTTGGATCTGAATC AACTTCAGGCCTCCGTCTTTAACAATCACTTGAAT ATGGCACC G GGATCAGG 3010 CCTGATCC C GGTGCCAT 3011 Non-polyposis ATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGTTGATTCAGA 3012 colorectal cancer TCCAAGACAATGGCACC G GGATCAGGGTAAGTAAAACCTCAA Gly67Arg AGTAGCAGGATGTTTGTGCGCTTCATGGAAGAGTCA GGG-CGG TGACTCTTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGT 3013 TTTACTTACCCTGATCC C GGTGCCATTGTCTTGGATCTGAATC AACTTCAGGCCTCCCTCTTTAACAATCACTTGAAT ATGGCACC G GGATCAGG 3014 CCTGATCC C GGTGCCAT 3015 Non-polyposis ATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGTTGATTTCAGA 3016 colorectal cancer TCCAAGACAATGGCACC G GGATCAGGGTAAGTAAAACCTCAA Gly67Trp AGTAGCAGGATGTTTGTGCGCTTCATGGAAGAGTCA GGG-TGG TGACTCTTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGT 3017 TTTACTTACCCTGATCCC G GTGCCATTGTCTTGGATCTGAATC AACTTCAGGCCTCCCTCTTTAACAATCACTTGAAT ATGGCACC G GGATCAGG 3018 CCTGATCC C GGTGCCAT 3019 Non-polyposis GTAACATGATTATTTACTCATCTTTTGGTATCTAACAGAPAGA 3020 colorectal cancer AGATCTGGATATTGTA T GTGAAAGGTTCACTACTAGTAAACTG Cys77Arg CAGTCCTTTGAGGATTTAGCCAGTATTTCTACCT TGT-CGT AGGTAGAAATACTGGCTAAATCCTCAAAGGACTGCAGTTTACT 3021 AGTAGTGAACCTTTCAC A TACAATATCCAGATCTTTCTTTGTT AGATACCAAAAAGATGAGTAAATAATCATGTTAC ATATTGTA T GTGAAAGG 3022 CCTTTCAC A TACAATAT 3023 Non-polyposis TAACATGATTATTTACTCATCTTTTTGGTATCTAACAGAAGAA 3024 colorectal cancer GATCTGGATATTGTAT G TGAAAGGTTCACTACTAGTAAACTGC Cys77Tyr AGTCCTTTGAGGATTTAGCCAGTATTTCTACCTA TGT-TAT TAGGTAGAAATACTGGCTAAATCCTCAAAGGACTGCAGTTTAC 3025 TAGTAGTGAACCTTTCA C ATACAATATCCAGATCTTCTTTCTGT TAGATACCAAAAAGATGAGTAAATAATCATGTTA TATTGTAT G TGAAAGGT 3026 ACCTTTCA C ATACAATA 3027 Non-polyposis CTGGATATTGTATGTGAAAGGTTCACTACTAGTAAACTGCAGT 3028 colorectal cancer CCTTTGAGGATTTAGCC A GTATTTCTACCTATGGCTTTCGAGG Ser93Gly TGAGGTAAGCTAAAGATTCAAGAAATGTGTAAAAT AGT-GGT ATTTTACACATTTCTTGAATCTTTAGCTTACCTCACCTCGAAAG 3029 CCATAGGTAGAAATAC T GGCTAAATCCTCAAAGGACTGCAGTT TACTAGTAGTGAACCTTTCACATACAATATCCAG ATTTAGCC A GTATTTCT 3030 AGAAATAC T GGCTAAAT 3031 Non-polyposis TTCACTACTAGTAAACTGCAGTCCTTTGAGGATTTAGCCAGTA 3032 colorectal cancer TTTCTACCTATGGCTTT C GAGGTGAGGTAAGCTAAAGATTCAA Arg100Term GAAATGTGTAAAATATCCTCCTGTGATGACATTGT CGA-TGA ACAATGTCATCACAGGAGGATATTTTACACATTTCTTGAATCTT 3033 TAGCTTACCTCACCTC G AAAGCCATAGGTAGAAATACTGGCTA AATCCTCAAAGGACTGCAGTTTACTAGTAGTGAA ATGGCTTT C GAGGTGAG 3034 CTCACCTC G AAAGCCAT 3035 Non-polyposis ACCCAGCAGTGAGTTTTTCTTTCAGTCTATTTTCTTTTCTTCCT 3036 colorectal cancer TAGGCTTTGGCCAGCA T AAGCCATGTGGCTCATGTTACTATTA Ile107Arg CAACGAAAACAGCTGATGGAAAGTGTGCATACAG ATA-AGA CTGTATGCACACTTTCCATCAGCTGTTTTCGTTGTAATAGTAA 3037 CATGAGCCACATGGCTT A TGCTGGCCAAAGCCTTAGGAAGAA AAGAAAATAGACTGAAAGAAAAACTCACTGCTGGGT GGCCAGCA T AAGCCATG 3038 CATGGCTT A TGCTGGCC 3039 Non-polyposis TTTCTTTTCTTCCTTAGGCTTTGGCCAGCATAAGCCATGTGGC 3040 colorectal cancer TCATGTTACTATTACAA C GAAAACAGCTGATGGAAAGTGTGCA Thr117Arg TACAGGTATAGTGCTGACTTCTTTTACTCATATAT ACG-AGG ATATATGAGTAAAAGAAGTCAGCACTATACCTGTATGCACACT 3041 TTCCATCAGCTGTTTTC G TTGTAATAGTAACATGAGCCACATG GCTTATGCTGGCCAAAGCCTAAGGAAGAAAAGAAA TATTACAA C GATAAACAG 3042 CTGTTTTC G TTGTAATA 3043 Non-polyposis TTTCTTTTCTTCCTTAGGCTTTGGCCAGCATAAGCCATGTGGC 3044 colorectal cancer TCATGTTACTATTACAA C GAAAACAGCTGATGGAAAGTGTGCA Thr117Met TACAGGTATAGTGCTGACTTCTTTTACTCATATAT ACG-ATG ATATATGAGTTAAAAGAAGTCAGCACTATACCTGTATGCACACT 3045 TTCCATCAGCTGTTTTC G TTGTAATAGTAACATGAGCCACATG GCTTATGCTGGCCAAAGCGTAAGGAAGAAAAGAAA TATTACAA C GAAAACAG 3046 CTGTTTTC G TTGTAATA 3047 Non-polyposis TCTATCTCTCTACTGGATATTAATTTGTTATATTTTCTCATTAGA 3048 colorectal cancer GCAAGTTACTCAGAT G GAAAACTGAAAGCCCCTCCTAAACCA Gly133Term TGTGCTGGCAATCAAGGGACCCAGATCACGGTAA GGA-TGA TTACCGTGATCTGGGTCCCTTGATTGCCAGCACATGGTTTAG 3049 GAGGGGCTTTCAGTTTTC C ATCTGAGTAACTTGCTCTAATGAG ATAAATATAACAAATTAATATCCAGTAGAGAGATAGA ACTCAGAT G GAAAACTG 3050 CAGTTTTC C ATCTGAGT 3051 Non-polyposis TAGTGTGTGTTTTTGGCAACTCTTTTCTTACTCTTTTGTTTTTC 3052 colorectal cancer TTTTCCAGGTATTCAG T ACACAATGCAGGCATTAGTTTTCTCAG Val185Gly TTAAAAAAGTAAGTTCTTGGTTTATGGGGGATGG GTA-GGA CCATCCCCCATAAACCAAGAAGTTACTTTTTTAACTGAGAAAC 3053 TAATGCCTGCATTGTGT A CTGAATACCTGGAAAAGAATAAACAA AAGAGTAAGTAAAAGAGTTGCCAAAAACACACACTA GTATTCAG T ACACAATG 3054 CATTGTGT A CTGAATAC 3055 Non-polyposis TTTCTTACTCTTTTGTTTTTCTTTTCCAGGTATTCAGTACACAAT 3056 colorectal cancer GCAGGCATTAGTTTC T CAGTTAAAAAAGTAAGTTCTTGGTTTAT Ser193Pro GGGGGATGGTTTTGTTTTATGTAAAAGAAAAAA TCA-CCA TTTTTTCTTTTCATAAAACAAAACCATCCCCCATAAACCAAGAA 3057 CTTACTTTTTTAACT G AGAAACTAATGCCTGCATTGTGTACTG AATACCTGGAAAAGAAAAACAAAAGAGTAAGAAA TTAGTTTC T CAGTTAAA 3058 TTTAACTG A GAAACTAA 3059 Non-polyposis TTTGTTTATCAGCTAGGAGAGACAGTAGCTGATGTTAGGACA 3060 colorectal cancer CTACCCAATGCCTCAACC G TGGACAATATTCGCTCCATCTTTG GAAATGCTGTTAGTCGGTATGTCGATAACCTATATA TATATAGGTTATCGACATACCGACTAACAGCATTTCCAAAGAT 3061 GGAGCGAATATTGTCCA C GGTTGAGGCATTGGGTAGTGTCCT AACATCAGCTACTGTCTCTCCTTGCTGATAAACAAA CCTCAACC G TGGACAAT 3062 ATTGTCCA C GGTTGAGG 3063 Non-polyposis CAAGGAGAGACAGTAGCTGATGTTAGGACACTACCCAATGCC 3064 colorectal cancer TCAACCGTGGACAATATT C GCTCCATCTTTGGAAATGCTGTTA Arg217Cys GTCGGTATGTCGATAACCTATATAAAAAAAATCTTTT CGC-TGC AAAAGATTTTTTTATATAGGTTATCGACATACCGACTAACAGCA 3065 TTTCCAAAGATGGAGC G AATATTGTCCACGGTTGAGGCATTG GGTAGTGTCCTAACATCAGCTACTGTCTCTCCTTG ACAATATT C GCTCCATC 3066 GATGGAGC G AATATTGT 3067 Non-polyposis GAGACAGTAGCTGATGTTAGGACACTACCCAATGCCTCAACC 3068 colorectal cancer GTGGACAATATTCGCTCC A TCTTTGGAAATGCTGTTAGTCGGT Ile219Val ATGTCGATAACCTATATAAAAAAATCTTTTACATTT ATC-GTC AAATGTAAAAGATTTTTTTATATAGGTTATCGACATACCGACTA 3069 ACAGCATTTCCAAAGA T GGAGCGAATATTGTCCACGGTTGAG GCATTGGGTAGTGTCCTAACATCAGCTACTGTCTC TTCGCTCC A TCTTTGGA 3070 TCCAAAGA T GGAGCGAA 3071 Non-polyposis CTAATAGAGAACTGATAGTAAATTGGATGTGAGGATAAAACCCT 3072 colorectal cancer AGCCTTCAAAATGAATG G TTACATATCCAATGCAAACTACTCA Gly244Asp GTGAAGAAGTGCATCTTCTTACTCTTCATCAACCG GGT-GAT CGGTTGATGAAGAGTAAGAAGATGCACTTCTTCACTGAGTAG 3073 TTTGCATTGGATATGTAA C CATTCATTTTGAAGGCTAGGGTT TATCCTCACATCCAATTTCTATCAGTTCTCTATTAG AATGAATG G TTACATAT 3074 ATATGTAA C CATTCATT 3075 Non-polyposis GATGTGAGGATAAAACCCTAGCCTTCAAPATGAATGGTTACAT 3076 colorectal cancer ATCCAATGCAAACTACT C AGTGAAGAAGTGCATCTCTTACTC Ser252Term TTCATCAACCGTAAGTTAAAAAGAACCACATGGGA TCA-TAA TCCCATGTGGTTCTTTTTAACTTACGGTTGATGAAGAGTAAGA 3077 AGATGCACTTCTTCACT G AGTAGTTTGCATTGGATATGTAACC ATTCATTTTGAAGGCTAGGGTTTTATCCTCACATC AAACTACT C AGTGAAGA 3078 TCTTCACT G AGTAGTTT 3079 Non-polyposis CACCCCTCAGGACAGTTTTGAACTGGTTGCTTTCTTTTTATTG 3080 colorectal cancer TTTAGATCGTCTGGTAG A ATCAACTTCCTTGAGAAAAGCCATA Glu268Gly GAAACAGTGTATGCAGCCTATTTGCCCAAAAACAC GAA-GGA GTGTTTTTGGGCAAATAGGCTGCATACACTGTTTCTATGGCTT 3081 TTCTCAAGGAAGTTGAT T CTACCAGACGATCTAAACAATAAAA AGAAAGCAACCAGTTCAAAACTGTCCTGAGGGGTG TCTGGTAG A ATCAACTT 3082 AAGTTGAT T CTACCAGA 3083 Non-polyposis CCCTCAGGACAGTTTTGAACTGGTTGCTTTCTTTTTATTGTTTA 3084 colorectal cancer GATCGTCTGGTAGAAT C AACTTCCTTGAGTAAAGCCATAGAAA Ser269Term CAGTGTATGCAGCCTATTTGCCCAAAAACACACA TCA-TGA TGTGTGTTTTTGGGCAAATAGGCTGCATACACTGTTTCTATGG 3085 CTTTTCTCAAGGAAGTT G ATTCTACCAGACGATCTAAACAATA AAAAGAAAGCAACCAGTTCAAAACTGTCCTGAGGG GGTAGAAT C AACTTCCT 3086 AGGAAGTT G ATTCTACC 3087 Non-polyposis CTTTTTCTCCCCCTCCCACTATCTAAGGTAATTGTTCTCTCTTA 3088 colorectal cancer TTTTCCTGACAGTTTA G AAATCAGTCCCCAGAATGTGGATGTT Glu297Term AATGTGCACCCCACTAAAGCATGAAGTTCACTTCC GAA-TAA GGAAGTGAACTTCATGCTTTGTGGGGTGCACATTAACATCCA 3089 CATTCTGGGGACTGATTT C TAAACTGTCAGGAAAATAAGAGAG AACAATTACCTTAGATAGTGGGAGGGGGAGAAAAAG ACAGTTTA G AAATCAGT 3090 ACTGATTT C TAAACTGT 3091 Non-polyposis CTCCCACTATCTAAGGTAATTGTTCTCTCTTATTTTCCTGACAG 3092 colorectal cancer TTTAGAAATCAGTCCC C AGAATGTGGATGTTAATGTGCACCCC Gln301Term ACAAAGCATGAAGTTCACTTCCTGCACGAGGAGA CAG-TAG TCTCCTCGTGCAGGAAGTGAACTTCATGCTTTGTGGGGTGCA 3093 CATTAACATCCACATTCT G GGGACTGATTTCTAAACTGTCAGG AAAATAAGAGAGAACAATTACCTTAGATAGTGGGAG TCAGTCCC C AGAATGTG 3094 CACATTCT G GGGACTGA 3095 Non-polyposis ATGTGCACCCCACAAAGCATGAAGTTCACTTCGTGCACGAGG 3096 colorectal cancer AGAGCATCCTGGAGCGGG T GCAGCAGCACATCGAGAGCAAG Val326Ala CTCCTGGGCTCCAATTCCTCCAGGATGTACTTCACCCA GTG-GCG TGGGTGAAGTACATCCTGGAGGAATTGGAGCCCAGGAGCTT 3097 GCTCTCGATGTGCTGCTGC A CCCGCTCCAGGATGCTCTCCT CGTGCAGGAAGTGAACTTCATGCTTTGTGGGGTGCACAT GGAGCGGG T GCAGCAGC 3098 GCTGCTGC A CCCGCTCC 3099 Non-polyposis CCACAAAGCATGAAGTTCACTTCCTGCACGAGGAGAGCATCC 3100 colorectal cancer TGGAGCGGGTGCAGCAGC A CATCGAGAGCAAGCTCCTGGGC His329Pro TCCAATTCCTCCAGGATGTACTTCACCCAGGTCAGGGC CAC-CCC GCCCTGACCTGGGTGAAGTACATCCTGGAGGAATTGGAGCC 3101 CAGGAGCTTGCTCTCGATG T GCTGCTGCACCCGCTCCAGGA TGCTCTCCTCGTGCAGGAAGTGAACTTCATGCTTTGTGG GCAGCAGC A CATCGAGA 3102 TCTCGATG T GCTGCTGC 3103 Non-polyposis CAAGTCTGACCTCGTCTTCTACTTCTGGAAGTAGTGATAAGGT 3104 colorectal cancer CTATGCCCACCAGATGG T TCGTACAGATTCCCGGGAACAGAA Val384Asp GCTTGATGCATTTCTGCAGCCTCTGAGCAAACCCCT GTT-GAT AGGGGTTTGCTCAGAGGCTGCAGAAATGCATCAAGCTTCTGT 3105 TCCCGGGAATCTGTACGA A CCATCTGGTGGGCATAGACCTTA TCACTACTTCCAGAAGTAGAAGACGAGGTCAGACTTG CCAGATGG T TCGTACAG 3106 CTGTACGA A CCATCTGG 3107 Non-polyposis AGTGGCAGGGCTAGGCAGCAAGATGAGGAGATGCTTGAACT 3108 colorectal cancer CCCAGCCCCTGCTGAAGTG G CTGCCAAAAATCAGAGCTTGGA Ala441Thr GGGGGATACAACAAAGGGGACTTCAGAAATGTCAGAGA GCT-ACT TCTCTGACATTTCTGAAGTCCCCTTTGTTGTATCCCCCTCCAA 3109 GCTCTGATTTTTGGCAG C CACTTCAGCAGGGGCTGGGAGTTC AAGCATCTCCTCATCTTGCTGCCTAGCCCTGCCACT CTGAAGTG G CTGCCAAA 3110 TTTGGCAG C CACTTCAG 3111 Non-polyposis CTTCATTGCAGAAAGAGACATCGGGAAGATTCTGATGTGGAA 3112 colorectal cancer ATGGTGGAAGATGATTCC C GAAAGGAAATGACTGCAGCTTGT Arg487Term ACCCCCCGGAGAAGGATCATTAACCTCACTAGTGTTT CGA-TGA AAACACTAGTGAGGTTAATGATCCTTCTCCGGGGGGTACAAG 3113 CTGCAGTCATTTCCTTTC G GGAATCATCTTCCACCATTTCCAC ATCAGAATCTTCCCGATGTCTCTTTCTGCAATGAAG ATGATTCC C GTAAAGGAA 3114 TTCCTTTC G GGAATCAT 3115 Non-polyposis AGACATCGGGAAGATTCTGATGTGGAAATGGTGGAAGATGAT 3116 colorectal cancer TCCCGAAAGGAAAT G ACTGCAGCTTGTACCCCCCGGAGAAG Ala492Thr GATCATTAACCTCACTAGTGTTTTGAGTCTCCAGGAAG GCA-ACA CTTCCTGGAGACTCAAAACACTAGTGAGGTTAATGATCCTTCT 3117 CCGGGGGGTACAAGCTG C AGTCATTTCCTTTCGGGAATCATC TTCCACCATTTCCACATCAGAATCTTCCCGATGTCT AAATGACT G CAGCTTGT 3118 ACAAGCTG C AGTCATTT 3119 Non-polyposis CCCGAAAGGAAATGACTGCAGCTTGTACCCCCCGGAGAAGG 3120 colorectal cancer ATCATTAACCTCACTAGTG T TTTGAGTCTCCAGGAAGAAATTA Val506Ala ATGAGCAGGGACATGAGGGTACGTAAACGCTGTGGCC GTT-GCT GGCCACAGCGTTTACGTACCCTCATGTCCCTGCTCATTAATTT 3121 CTTCCTGGAGACTCAAA A CACTAGTGAGGTTAATGATCCTTCT CCGGGGGGTACAAGCTGCAGTCATTTCCTTTCGGG CACTAGTG T TTTGAGTC 3122 GACTCAAA A CACTAGTG 3123 Non-polyposis GGGAGATGTTGCATAACCACTCCTTCGTGGGCTGTGTGTGAATC 3124 colorectal cancer CTCAGTGGGCCTTGGCAC A GCATCAAACCAAGTTATACCTTCT Gln542Leu TTCAACACCACCAAGCTTAGGTAAATCAGCTGAGTGTG CAG-CTG CACACTCAGCTGATTTACCTAAGCTTGGTGGTGTTGAGAAGG 3125 TATAACTTGGTTTGATGC T GTGCCAAGGCCCACTGAGGATTC ACACAGCCCACGTAGGAGTGGTTATGCTACATCTCCC CTTGGCAC A GCATCAAA 3126 TTTGATGC T GTGCCAAG 3127 Non-polyposis CCTTCGTGGGCTGTGTGAATCCTCAGTGGGCCTTGGCACAG 3128 colorectal cancer CATCAAACCAAGTTATACC T TCTCAACACCACCAAGCTTAGGT Leu549Pro AAATCAGCTGAGTGTGTGAACAAGCAGAGCTACTACA CTT-CCT TGTAGTAGCTCTGCTTGTTCACACACTCAGCTGATTTACCTAA 3129 GCTTGGTGGTGTTGAGA A GGTATAACTTGGTTTGATGCTGTG CCAAGGCCCACTGAGGATTCACACAGCCCACGAAGG GTTATACC T TCTCAACA 3130 TGTTGAGA A GGTATAAC 3131 Non-polyposis TGGGCTGTGTGAATCCTCAGTGGGCCTTGGCACAGCATCAAA 3132 colorectal cancer CCAAGTTATACCTTCTCA A CACCACCAAGCTTAGGTAAATCAG Asn551Thr CTGAGTGTGTGAACAAGCAGAGCTACTACAACAATG AAC-ACC CATTGTTGTAGTAGCTCTGCTTGTTCACACACTCAGCTGATTT 3133 ACCTAAGCTTGGTGGTG T TGAGAAGGTATAACTTGGTTTGATG CTGTGCCAAGGCCCACTGAGGATTCACACAGCCCA CCTTCTCA A CACCACCA 3134 TGGTGGTG T TGAGAAGG 3135 Non-polyposis ATGAATTCAGCTTTTCCTTAAAGTCACTTCATTTTTATTTTCAG 3136 colorectal cancer TGAAGAACTGTTCTAC C AGATACTCATTTATGATTTTGCCAATT Gln562Term TTGGTGTTCTCAGGTTATCGGTAAGTTTAGATC CAG-TAG GATCTAAACTTACCGATAACCTGAGAACACCAAAATTGGCAAA 3137 ATCATAAATGAGTATCT G GTAGAACAGTTCTTCACTGAAAATA AAAATGAAGTGACTTTAAGGAAAAGCTGAATTCAT TGTTCTAC C AGATACTC 3138 GAGTATCT G GTAGAACA 3139 Non-polyposis GCTTTTCCTTAAAGTCACTTCATTTTTATTTTCAGTGAAGAACT 3140 colorectal cancer GTTCTACCAGATACTC A TTTATGATTTTGCCAATTTTGGTGTTC Ile565Phe TCAGGTTATCGGTAAGTTTAGATCCTTTTCACT ATT-TTT AGTGAAAAGGATCTAAACTTACCGATAACCTGAGAACACCAAA 3141 ATTGGCAAAATCATAAA T GAGTATCTGGTAGAACAGTTCTTCA CTGAAAATAAAAATGAAGTGACTTTAAGGAAAAGC AGATACTC A TTTATGAT 3142 ATCATAAA T GAGTATCT 3143 Non-polyposis TTTTCAGTGAAGAACTGTTCTACCAGATACTCATTTATGATTTT 3144 colorectal cancer GCCAATTTTGGTGTTC T CAGGTTATCGGTAAGTTTAGATCCTT Leu574Pro TTCACTTCTGAAATTTCAACTGATCGTTTCTGAA CTC-CCC TTCAGAAACGATCAGTTGAAATTTCAGAAGTGAAAAGGATCTA 3145 AACTTACCGATAACCTG A GAACACCAAAATTGGCAAAATCATA AATGAGTATCTGGTAGAACAGTTCTTCACTGAAAA TGGTGTTC T CAGGTTAT 3146 ATAACCTG A GAACACCA 3147 Non-polyposis TGGATGCTCCGTTTAAAGCTTGCTCCTTCATGTTCTTGCTTCTT 3148 colorectal cancer CCTAGGAGCCAGCACCG C TCTTTGACCTTGCCATGCTTGCCT Leu582Val TAGATAGTCCAGAGAGTGGCTGGACAGAGGAAGATG CTC-GTC CATCTTCCTCTGTCCAGCCACTCTCTGGACTATCTAAGGCAA 3149 GCATGGCAAGGTCAAAGA G CGGTGCTGGCTCCTAGGAAGAA GCAAGAACATGAAGGAGCAAGCTTTAACGGAGCATCCA CAGCACCG C TCTTTGAC 3150 GTCAAAGA G CGGTGCTG 3151 Non-polyposis TGCTTGCCTTAGATAGTCCAGAGAGTGGCTGGACAGAGGAAG 3152 colorectal cancer ATGGTCCCAAAGAAGGAC T TGCTGAATACATTGTTGAGTTTCT Leu607His GAAGAAGAAGGCTGAGATGCTTGCAGACTATTTCTC CTT-CAT GAGAAATAGTCTGCAAGCATCTCAGCCTTCTTCTTCAGAAACT 3153 CAACAATGTATTCAGCA A GTCCTTCTTTGGGACCATCTTCCTC TGTCCAGCCACTCTCTGGACTATCTAAGGCAAGCA AGAAGGAC T TGCTGAAT 3154 ATTCAGCA A GTCCTTCT 3155 Non-polyposis ACAGAGGAAGATGGTCCCAAAGAAGGACTTGCTGAATACATT 3156 colorectal cancer GTTGAGTTTCTGAAG A AGAAGGCTGAGATGCTTGCAGACTAT Lys618Term TTCTCTTTGGAAATTGATGAGGTGTGACAGCCATTCT AAG-TAG AGTATGGCTGTCACACCTCATCAATTTCCAAAGAGAAATAGTC 3157 TGCAAGCATCTCAGCCT T CTTCTTCAGAAACTCAACAATGTAT TCAGCAAGTCCTTCTTTGGGACCATCTTCCTCTGT TGAAGAAG A AGGCTGAG 3158 CTCAGCCT T CTTCTTCA 3159 Non-polyposis CAGAGGAAGATGGTCCCAAAGAAGGACTTGCTGAATACATTG 3160 colorectal cancer TTGAGTTTCTGAAGAAGA A GGCTGAGATGCTTGCAGACTATTT Lys618Thr CTCTTTGGAAATTGATGAGGTGTGACAGCCATTCTT AAG-ACG AAGAATGGCTGTCACACCTCATCAATTTCCAAAGAGAAATAGT 3161 CTGCAAGCATCTCAGCC T TCTTCTTCAGAAACTCAACAATGTA TTCAGCAAGTCCTTCTTTGGGACCATCTTCCTCTG GAAGAAGA A GGCTGAGA 3162 TCTCAGCC T TCTTCTTC 3163 Non-polyposis TACCCCTTCTGATTGACAACTATGTGCCCCCTTTGGAGGGAC 3164 colorectal cancer TGCCTATCTTCATTCTTC G ACTAGCCACTGAGGTCAGTGATCA Arg659Leu AGCAGATACTAAGCATTTCGGTACATGCATGTGTGC CGA-CTA GCACACATGCATGTACCGAAATGCTTAGTATCTGCTTGATCAC 3165 TGACCTCAGTGGCTAGT C GAAGAATGAAGATAGGCAGTCCCT CCAAAGGGGGCACATAGTTGTCAATCAGAAGGGGTA CATTCTTC G ACTAGCCA 3166 TGGCTAGT C GAAGAATG 3167 Non-polyposis TACCCCTTCTGATTGACAACTATGTGCCCCCTTTGGAGGGAC 3168 colorectal cancer TGCCTATCTTCATTCTTC G ACTAGCCACTGAGGTCAGTGATCA Arg659Pro AGCAGATACTAAGCATTTCGGTACATGCATGTGTGC CGA-CCA GCACACATGCATGTACCGAAATGCTTAGTATCTGCTTGATCAC 3169 TGACGTCAGTGGCTAGT C GAAGAATGAAGATAGGCAGTCCCT CCTAAAGGGGGCACATAGTTGTCAATCAGAAGGGGTA CATTCTTC G ACTAGCCA 3170 TGGCTAGT C GAAGAATG 3171 Non-polyposis TTACCCCTTCTGATTGACAACTATGTGCCCCCTTTGGAGGGA 3172 colorectal cancer CTGCCTATCTTCATTCTT C GACTAGCCACTGAGGTCAGTGATC Arg659Term AAGCAGATACTAAGCATTTCGGTACATGCATGTGTG CGA-TGA CACACATGCATGTACCGAAATGCTTAGTATCTGCTTGATCACT 3173 GACCTCAGTGGCTAGTC G AAGAATGAAGATAGGCAGTCCCTC CAAAGGGGGCACATAGTTGTCAATCAGAAGGGGTAA TCATTCTT C GACTAGCC 3174 GGCTAGTC G AAGAATGA 3175 Non-polyposis TTGGACCAGGTGAATTGGGACGAAGAAAAGGAATGTTTTGAA 3176 colorectal cancer AGCCTCAGTAAAGAATG C GCTATGTTCTATTCCATCCGGAAG Ala681Thr CAGTACATATCTGAGGAGTCGACCCTCTCAGGCCAGC GCT-ACT GCTGGCCTGAGAGGGTCGACTCCTCAGATATGTACTGCTTCC 3177 GGATGGAATAGAACATAG C GCATTCTTTACTGAGGCTTTCAAA ACATTCCTTTTCTTCGTCCCAATTCACCTGGTCCAA AAGAATGC G CTATGTTC 3178 GAACATAG C GCATTCTT 3179 Non-polyposis AGGCTTATGACATCTAATGTGTTTTCCAGAGTGAAGTGCCTGG 3180 colorectal cancer CTCCATTCCPAACTCCT G GAAGTGGACTGTGGAACACATTGT Trp712Term CTATAAAGCCTTGCGCTCACACATTCTGCCTCCTAA TGG-TAG TTAGGAGGCAGAATGTGTGAGCGCAAGGCTTTATAGACAATG 3181 TGTTCCACAGTCCACTTC C AGGAGTTTGGAATGGAGCCAGGC ACTTCACTCTGGAAAACACATTAGATGTCATAAGCCT AAACTCCT G GAAGTGGA 3182 TCCACTTC C AGGAGTTT 3183 Non-polyposis ATGACATCTAATGTGTTTTCCAGAGTGAAGTGCCTGGCTCCAT 3184 colorectal cancer TCCAAACTCCTGGAAGT G GACTGTGGAACACATTGTCTATAAA Trp714Term GCCTTGCGCTCACACATTCTGCCTCCTAAACATTT TGG-TAG AAATGTTTAGGAGGCAGAATGTGTGAGCGCAAGGCTTTATAG 3185 ACAATGTGTTCCACAGTC C ACTTCCAGGAGTTTGGAATGGAG CCAGGCACTTCACTCTGGAAAACACATTAGATGTCAT CTGGAAGT G GACTGTGG 3186 CCACAGTC C ACTTCCAG 3187 Non-polyposis TGACATCTAATGTGTTTTCCAGAGTGAAGTGCCTGGCTCCATT 3188 colorectal cancer CCAAACTCCTGGAAGTG G ACTGTGGAACACATTGTCTATAAA Trp714Term GCCTTGCGCTCACACATTCTGCCTCCTAAACATTTC TGG-TGA GAAATGTTTAGGAGGCAGAATGTGTGAGCGCAAGGCTTTATA 3189 GACAATGTGTTCCACAGT C CACTTCCAGGAGTTTGGAATGGA GCCAGGCACTTCACTCTGGAAkACACATTAGATGTCA TGGAAGTG G ACTGTGGA 3190 TCCACAGT C CACTTCCA 3191 Non-polyposis ATCTAATGTGTTTTCCAGAGTGAAGTGCCTGGCTCCATTCCAA 3192 colorectal cancer ACTCCTGGAAGTGGACT G TGGAACACATTGTCTATAAAGCCTT Val716Met GCGCTCACACATTCTGCCTCCTAAACATTTCACAG GTG-ATG CTGTGAAATGTTTAGGAGGCAGAATGTGTGAGCGCAAGGCTT 3193 TATAGACAATGTGTTCCA C AGTCCACTTCCAGGAGTTTGGAAT GGAGCCAGGCACTTCACTCTGGAAAACACATTAGAT AGTGGACT G TGGAACAC 3194 GTGTTCCA C AGTCCACT 3195 Non-polyposis GAGTGAAGTGCCTGGCTCCATTCCAAACTCCTGGAAGTGGAC 3196 colorectal cancer TGTGGAACACATTGTCTA T AAAGCCTTGCGCTCACACATTCTG Tyr721Term CCTCCTAAACATTTCACAGAAGATGGAAATATCCTG TAT-TAA CAGGATATTTCCATCTTCTGTGAAATGTTTAGGAGGCAGAATG 3197 TGTGAGCGCAAGGCTTT A TAGACAATGTGTTCCACAGTCCAC TTCCAGGAGTTTGGAATGGAGCCAGGCACTTCACTC ATTGTCTA T AAAGCCTT 3198 AAGGCTTT A TAGACAAT 3199 Non-polyposis CTAAACATTTCACAGAAGATGGAAATATCCTGCAGCTTGCTAA 3200 colorectal cancer CCTGCCTGATCTATACA A AGTCTTTGAGAGGTGTTAAATATGG Lys751Arg TTATTTATGCACTGTGGGATGTGTTCTTCTTTCTC AAA-AGA GAGTAAGAAGAACACATCCCACAGTGCATAAATAACCATATTT 3201 AACACCTCTCAAAGACT T TGTATAGATCAGGCAGGTTAGCAAG CTGCAGGATATTTCCATCTTCTGTGAAATGTTTAG TCTATACA A AGTCTTTG 3202 CAAAGACT T TGTATAGA 3203 Non-polyposis ACAGAAGATGGAAATATCCTGCAGCTTGCTAACCTGCCTGAT 3204 colorectal cancer CTATACAAAGTCTTTGAG A GGTGTTAAATATGGTTATTTATGCA Arg755Trp CTGTGGGATGTGTTCTTCTTTCTCTGTATTCCGAT AGG-TGG ATCGGAATACAGAGAAAGAAGAACACATCCCAGAGTGCATAA 3205 ATAACCATATTTAACACC T CTCAAAGACTTTGTATAGATCAGG CAGGTTAGCAAGCTGCAGGATATTTCCATCTTCTGT TCTTTGAG A GGTGTTAA 3206 TTAACACC T CTCAAAGA 3207

EXAMPLE 18 Human Mismatch Repair—MSH2

The human MSH2 gene is homologous to the bacterial mutS gene, which is involved in mismatch repair. Mutations in the MSH2 gene have been identified in a variety of cancers, including, for example, ovarian tumors, colorectal cancer, endometrial cancer, uterine cancer. The attached table discloses the correcting oligonucleotide base sequences for the MSH2 oligonucleotides of the invention.

TABLE 25 MSH2 Mutations and Genome-Connecting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Non polyposis TTTTCCACAAAAGACATTTATCAGGACCTCAACCGGTTGTTGA 3208 colorectal cancer AAGGCAAAAAGGGAGAG C AGATGAATAGTGCTGTATTGCCAG Gln252Term AAATGGAGAATCAGGTACATGGATTATAAATGTGAA CAG-TAG TTCACATTTATAATCCATGTACCTGATTCTCCATTTCTGGCAAT 3209 ACAGCACTATTCATCT G CTCTCCCTTTTTGCCTTTCAACAACC GGTTGAGGTCCTGATAAATGTCTTTTGTGGAAAA AGGGAGAG C AGATGAAT 3210 ATTCATCT G CTCTCCCT 3211 Non polyposis TCATCACTGTCTGCGGTAATCAAGTTTTTAGAACTCTTATCAG 3212 colorectal cancer ATGATTCCAACTTTGGA C AGTTTGAACTGACTACTTTTGACTT Gln288Term CAGCCAGTATATGAAATTGGATATTGCAGCAGTCA CAG-TAG TGACTGCTGCAATATCCAATTTCATATACTGGCTGAAGTCAAA 3213 AGTAGTCAGTTCAAACT G TCCAAAGTTGGAATCATCTGATAAG AGTTCTAAAAACTTGATTACCGCAGACAGTGATGA ACTTTGGA C AGTTTGAA 3214 TTCAAACT G TCCAAAGT 3215 Non polyposis AACTTTGGACAGTTTGAACTGACTACTTTTGACTTCAGCCAGT 3216 colorectal cancer ATATGAAATTGGATATT G CAGCAGTCAGAGCCCTTAACCTTTT Ala305Thr TCAGGTAAAAAAAAAAAAAAAAAAAAAAAAAAAGG GCA-ACA CCTTTTTTTTTTTTTTTTTTTTTTTTTACCTGAAAAAGGTTAAG 3217 GGCTCTGACTGCTG C AATATCCAATTTCATATACTGGCTGAAG TCAAAAGTAGTCAGTTCAAACTGTCCAAAGTT TGGATATT G CAGGAGTC 3218 GACTGCTG C AATATCCA 3219 Non polyposis AGCTTGCCATTCTTTCTATTTTATTTTTTGTTTACTAGGGTTCT 3220 colorectal cancer GTTGAAGATACCACTG G CTCTCAGTCTCTGGCTGCCTTGCTG Gly322Asp AATAAGTGTAAAACCCCTCAAGGACAAAGACTTGT GGC-GAC ACAAGTCTTTGTCCTTGAGGGGTTTTACACTTATTCAGCAAGG 3221 CAGCCAGAGACTGAGAG C CAGTGGTATCTTCAACAGAACCCT AGTAAACAAAAAATAAAATAGAAAGAATGGCAAGCT TACCACTG G CTCTCAGT 3222 ACTGAGAG C CAGTGGTA 3223 Non polyposis TTGCCATTCTTTCTATTTTATTTTTTGTTTACTAGGGTTCTGTTG 3224 colorectal cancer AAGATACCACTGG C TCTCAGTCTGTGGCTGGCTTGCTGAATA Ser323Cys AGTGTAAAACCCCTCAAGGACAAAGACTTGTTAA TCT-TGT TTAACAAGTCTTTGTCCTTGAGGGGTTTTACACTTATTCAGCA 3225 AGGCAGCCAGAGACTGA G AGCCAGTGGTATCTTCAACAGAAC CCTAGTAAACAAAAAATAAAATAGAAAGAATGGCAA CACTGGCT C TCAGTCTC 3226 GAGACTGA G AGCCAGTG 3227 Non polyposis GTGGAAGCTTTTGTAGAAGATGCAGAATGAGGCAGACTTTA 3228 colorectal cancer CAAGAAGATTTACTTCGT C GATTCGCAGATCTTAACCGACTTG Arg383Term CCAAGAAGTTTCAAAGACAAGCAGCAAACTTACAAG CGA-TGA CTTGTAAGTTTGCTGCTTGTCTTTGAAACTTCTTGGCAAGTCG 3229 GTTAAGATCTGGGAATC G ACGAAGTAAATCTTCTTGTAAAGTC TGCCTCAATTCTGCATCTTCTACAAAAGCTTCCAC TACTTCGT C GATTCCCA 3230 TGGGAATC G ACGAAGTA 3231 Non polyposis CAAGAAGATTTACTTCGTCGATTCCCAGATCTTAACCGACTTG 3232 colorectal cancer CCAAGAAGTTTCAAAGA C AAGCAGCAAACTTACAAGATTGTTA Gln397Term CCGACTCTATCAGGGTATAAAATCAACTACCTAATG CAA-TAA CATTAGGTAGTTGATTTATACCCTGATAGAGTCGGTAACAATC 3233 TTGTAAGTTTGCTGCTT G TCTTTGAAACTTCTTGGCAAGTCGG TTAAGATCTGGGAATCGACGAAGTAAATCTTCTTG TTCAAAGA C AAGCAGCA 3234 TGCTGCTT G TCTTTGAA 3235 Non polyposis GATCTTAACCGACTTGCCAAGAAGTTTCAAAGACAAGCAGCA 3236 colorectal cancer AACTTACAAGATTGTTAC C GACTCTATCAGGGTATAAATCAAC Arg406Term TACCTAATGTTATACAGGCTCTGGAAAAACATGAAG CGA-TGA CTTCATGTTTTTCCAGAGCCTGTATAACATTAGGTAGTTGATTT 3237 ATACCCTGATAGAGTC G GTAACAATCTTGTAAGTTTGCTGCTT GTCTTTGAAACTTCTTGGCAAGTCGGTTAAGATC ATTGTTAC C GACTCTAT 3238 ATAGAGTC G GTAACAAT 3239 Non polyposis GCAAACTTACAAGATTGTTACCGACTCTATCAGGGTATAAATC 3240 colorectal cancer AACTACCTAATGTTATA C AGGCTCTGGAAAATTACATGAAGGTAA Gln419Term CAAGTGATTTTGTTTTTTTGTTTTCTTCAACTCA CAG-TAG TGAGTTGAAGGAAAACAAAAAAACAAAATCACTTGTTACCTTC 3241 ATGTTTTTCGAGAGCCT G TATAACATTAGGTAGTTGATTTATAC CCTGATAGAGTCGGTAACAATCTTGTAAGTTTGC ATGTTATA C AGGCTCTG 3242 CAGAGCCT G TATAACAT 3243 Non polyposis TATTCTGTAAAATGAGATCTTTTTATTTGTTGTTTTACTACTTT 3244 colorectal cancer CTTTTAGGAAAACAC C AGAAATTATTGTTGGCAGTTTTTGTGA Gln429Term CTCCTCTTACTGATCTTCGTTCTGACTTCTCCA GAG-TAG TGGAGAAGTCAGAACGAAGATCAGTAAGAGGAGTCACAAAAA 3245 CTGCCAACAATAATTTCT G GTGTTTTCCTAAAAGAAAGTAGTA AAACAAACAAATAAAAAGATCTCATTTTACAGAATA GAAAACAC C AGAAATTA 3246 TAATTTT G GTGTTTTC 3247 Non polyposis CTCCTCTTACTGATCTTCGTTCTGACTTCTCCAAGTTTCAGGA 3248 colorectal cancer AATGATAGAAACAACTT T AGATATGGATCAGGTATGGAATATA Leu458Term CTTTTTAATTTAAGCAGTAGTTATTTTTAAAAAGC TTA-TGA GCTTTTTAAAAATAACTACTGCTTAAATTTAAAAGTATATTGCA 3249 TACCTGATCCATATCT A AAGTTGTTTCTATCATTTCCTGAAACT TGGAGAAGTCAGAACGAAGATCAGTAAGAGGAG AACAACTT T AGATATGG 3250 CCATATCT A AAGTTGTT 3251 Non polyposis TTTCTTCTTGATTATCAAGGCTTGGACCCTGGCAAAGAGATTA 3252 colorectal cancer AACTGGATTCCAGTGCA C AGTTTGGATATTACTTCGTGTAAC Gln518Term CTGTAAGGAAGAAAAAGTCCTTCGTAACAATAAAA CAG-TAG TTTTATTGTTACGAAGGACTTTTTCTTCCTTACAGGTTACACGA 3253 AAGTAATATCCAAACT G TGCACTGGAATCCAGTTTAATCTGTT TGCCAGGGTCCAAGCCTTGATAATCAAGAAGAAA CCAGTGCA C AGTTTGGA 3254 TCCAAACT G TGCACTGG 3255 Non polyposis GCTTGGACCCTGGCAAACAGATTAAACTGGATTCCAGTGCAC 3256 colorectal cancer AGTTTGGATATTACTTTC G TGTAACCTGTAAGGAAGAAAAAGT Arg524Pro CCTTCGTAACAATAAAAACTTTAGTACTGTAGATAT CGT-CCT ATATCTACAGTACTTAAAGTTTTTATTGTTACGAAGGACTTTTTC 3257 TTCCTTACAGGTTACA C GTAAAGTAATATCCAAACTGTGCACTG GAATCCAGTTTAATCTGTTTGCCAGGGTCCAAGC TTACTTTC G TGTAACCT 3258 AGGTTACA C GAAAGTAA 3259 Non polyposis TTAATATTTTTAATAAAACTGTTATTTCGATTTGCAGCAAATTGA 3260 colorectal cancer CTTCTTTAAATGAAG A GTATACCAAAAATAAAACAGAATATGAA Glu562Tal GAAGCCCAGGATGCCATTGTTAAAGAAATTGT GAG-GTG ACAATTTCTTTAACAATGGCATCCTGGGCTTCTTCATATTCTGT 3261 TTTATTTTTGGTATAC T CTTCATTTAAAGAAGTCAATTTGCTGC AAATCGAAATAACAGTTTTATTAAAAATATTAA AAATGAAG A GTATACCA 3262 TGGTATAC T CTTCATTT 3263 Glioma AATGAAGAGTATACCAAAAATAAAACAGAATATGAAGAAGCCC 3264 Glu580Term AGGATGCCATTGTAAA G AAATTGTCAATATTTGTTCAGGTAAA GAA-TAA CTTAATAGAACTAATAATGTTCTGAATGTCACCT AGGTGACATTCAGAACATTATTAGTTCTATTAAGTTTACCTGAA 3265 GAAATATTGACAATTT C TTTAAGAATGGCATCCTGGGCTTCTT CATATTCTGTTTTATTTTTGGTATACTCTTCATT TTGTTAAA G AAATTGTC 3266 GACAATTT C TTTAACAA 3267 Non polyposis TGTTTTTATTTTTATACAGGGTATGTAGAACCAATGCAGACACT 3268 colorectal cancer CAATGATGTGTTAGCT C AGCTAGATGCTGTTGTCAGCTTTGCT Gln601Term CACGTGTCAAATGGAGCACCTGTTCCATATGTAC CAG-TAG GTACATATGGAACAGGTGCTCCATTTGACACGTGAGCAAAGC 3269 TGACAACAGCATCTAGCT G AGCTAACACATCATTGAGTGTCTG CATTGGTTCTACATAGCCTGTATAAAAATAAAAACA TGTTAGCT C AGCTAGAT 3270 ATCTAGCT G AGCTAACA 3271 Non polyposis AGCTCAGCTAGATGCTGTTGTCAGCTTTGCTCACGTGTCAAAT 3272 colorectal cancer GGAGCACCTGTTCCAT A TGTACGACCAGCCATTTTGGAGAAA Tyr619Term GGACAAGGAAGAATTATATTAAAAGCATCCAGGCAT TAT-TAG ATGCCTGGATGCTTTTAATATAATTCTTCCTTGTCCTTTCTCCA 3273 AAATGGCTGGTCGTAC A TATGGAACAGGTGCTCCATTTGACA CGTGAGCAAAGCTGACAACAGCATCTAGCTGAGCT GTTCCATA T GTACGACC 3274 GGTCGTAC A TATGGAAC 3275 Non polyposis CAGCTAGATGCTGTTGTCAGCTTTGCTCACGTGTCAAATGGA 3276 colorectal cancer GCACCTGTTCCATATGT A CGACCAGCCATTTTGGAGAAAGGA Arg621Term CAAGGAAGAATTATATTAATAGCATCCAGGCATGCTT CGA-TGA AAGCATGCCTGGATGCTTTTAATATAATTCTTCCTTGTCCTTTC 3277 TCCAAAATGGCTGGTC G TACATATGGAACAGGTGCTCCATTT GACACGTGAGCAAAGCTGACAACAGCATCTAGCTG CATATGTA C GACCAGCC 3278 GGCTGGTC G TACATATG 3279 Non polyposis TAGATGCTGTTGTCAGCTTTGCTCAGGTGTCAAATGGAGCAC 3280 colorectal cancer CTGTTCCATATGTACGAC C AGCCATTTTGGAGAAAGGACAAG Pro622Leu GAAGAATTATATTAAAAGCATCCAGGCATGCTTGTGT CCA-CTA ACACAAGCATGCCTGGATGCTTTTAATATAATTCTTCCTTGTC 3281 CTTTCTCCAAAATGGCT G GTCGTACATATGGAACAGGTGCTC CATTTGACACGTGAGCAAAGCTGACAACAGCATCTA TGTACGAC C AGCCATTT 3282 AAATGGCT G GTCGTACA 3283 Non polyposis CCTGTTCCATATGTACGACCAGCCATTTTGGAGAAAGGACAA 3284 colorectal cancer GGAAGAATTATATTAAAA G CATCCAGGCATGCTTGTGTTGAAG Ala636Pro TTCAAGATGAAATTGCATTTATTCCTAATGACGTAT GCA-CCA ATACGTCATTAGGAATAAATGCAATTTCATCTTGAAGTTCAACA 3285 CAAGCATGCCTGGATG C TTTTAATATAATTCTTCCTTGTCCTTT CTCCAAAATGGCTGGTCGTACATATGGAACAGG TATTAAAA G CATCCAGG 3286 CCTGGATG C TTTTAATA 3287 Non polyposis ATGTACGACCAGCCATTTTGGAGAAAGGACAAGGAAGAATTA 3288 colorectal cancer TATTAAAAGCATCCAGGC A TGCTTGTGTTGAAGTTCAAGATGA TTis639Arg AATTGCATTTATTCCTAATGACGTATACTTTGAAAA CAT-CGT TTTTCAAAGTATACGTCATTAGGAATAAATGCAATTTCATCTTG 3289 AACTTCAACACAAGCA T GCCTGGATGCTTTTAATATAATTCTTC CTTGTCCTTTCTCCAAAATGGCTGGTCGTACAT ATCCAGGC A TGCTTGTG 3290 CACAAGCA T GCCTGGAT 3291 Non polyposis TATGTACGACCAGCCATTTTGGAGAAAGGACAAGGAAGAATT 3292 colorectal cancer ATATTAAAAGCATCCAGG C ATGCTTGTGTTGAAGTTCAAGATG TTis639Tyr AAATTGCATTTATTCCTAATGACGTATACTTTGAAA CAT-TAT TTTCAAAGTATACGTCATTAGGAATAAATGCAATTTCATCTTGA 3293 ACTTCAACACAAGCAT G CCTGGATGCTTTTAATATAATTCTTC CTTGTCCTTTCTCCAAAATGGCTGGTCGTACATA CATCCAGG C ATGCTTGT 3294 ACAAGCAT G CCTGGATG 3295 Non polyposis AAAGGACAAGGAAGAATTATATTAAAAGCATCCAGGCATGGTT 3296 colorectal cancer GTGTTGAAGTTCAAGAT G AAATTGCATTTATTCCTAATGACGT Glu647Lys ATACTTTGAAAAAGATAAACAGATGTTCCACATCA GAA-AAA TGATGTGGAACATCTGThTATCTTTTTCAAAGTATACGTCATTA 3297 GGAATAAATGCAATTT C ATCTTGAACTTCAACACAAGCATGCC TGGATGCTTTTAATATAATTCTTCCTTGTCCTTT TTCAAGAT G AAATTGCA 3298 TGCAATTT C ATCTTGAA 3299 Non polyposis ATCCAGGCATGCTTGTGTTGAAGTTCAAGATGAAATTGCATTT 3300 colorectal cancer ATTCCTAATGACGTATA C TTTGAAAAAGATAAACAGATGTTCCA Tyr656Term CATCATTACTGGTAAAAAACCTGGTTTTTGGGCT TAC-TAG AGCCCAAAAACCAGGTTTTTTACCAGTAATGATGTGGAACATC 3301 TGTTTATCTTTTTCAAA G TATACGTCATTAGGAATAAATGCAAT TTCATCTTGAACTTCAACACAAGCATGCCTGGAT GACGTATA C TTTGTAAAA 3302 TTTTCAAA G TATACGTC 3303 Non polyposis GAAAGAAGTTTAAAATCTTGCTTTCTGATATAATTTGTTTTGTA 3304 colorectal cancer GGCCCCAATATGGGAG G TAAATCAACATATATTCGACAAACT Gly674Asp GGGGTGATAGTACTCATGGCCCAAATTGGGTGTTT GGT-GAT AAACACCCAATTTGGGCCATGAGTAGTATCACCCCAGTTTGTC 3305 GAATATATGTTGATTTA C CTCCCATATTGGGGCCTACAAAACA AATTATATCAGAAAGCAAGATTTTAAACTTCTTTTC TATGGGAG G TAAATCAA 3306 TTGATTTA C CTCCCATA 3307 Non polyposis TTGCTTTCTGATATAATTTGTTTTGTAGGCCCCAATATGGGAG 3308 colorectal cancer GTAAATCAACATATATT C GACAAACTGGGGTGATAGTACTCAT Arg680Term GGCCCAAATTGGGTGTTTTGTGCCATGTGAGTCAG CGA-TGA CTGACTCACATGGCACAAAACACCCAATTTGGGCCATGAGTA 3309 CTATCACCCCAGTTTGTC G AATATATGTTGATTTACCTCCCAT ATTGGGGCCTACAAAACAAATTATATCAGAAAGCAA CATATATT C GACAAACT 3310 AGTTTGTC G AATATATG 3311 Non polyposis ATGGGAGGTAAATCAACATATATTCGACAAAACTGGGGTGATA 3312 colorectal cancer GTACTCATGGCCCAAATT G GGTGTTTTGTGCCATGTGAGTCA Gly692Arg GCAGAAGTGTCCATTGTGGACTGCATCTTAGCCCGAG GGG-CGG CTCGGGCTAAGATGCAGTCCACAATGGACACTTCTGCTGACT 3313 CACATGGCACAAAACACC C AATTTGGGCCATGAGTACTATCA CCCCAGTTTGTCGAATATATGTTGATTTACCTCCCAT CCCAAATT G GGTGTTTT 3314 AAAACACC C AATTTGGG 3315 Non polyposis ACATATATTCGACAAACTGGGGTGATAGTACTCATGGCCCAAA 3316 colorectal cancer TTGGGTGTTTTGTGCCA T GTGAGTCAGCAGAAGTGTCCATTG Cys697Arg TGGACTGCATCTTAGCCCGAGTAGGGGCTGGTGACA TGT-CGT TGTCACCAGCCCCTACTCGGGCTAAGATGCAGTCCACAATGG 3317 ACACTTCTGCTGACTCAC A TGGCACAAAACACCCAATTTGGG CCATGAGTACTATCACCCCAGTTTGTCGAATATATGT TTGTGCCA T GTGAGTCA 3318 TGACTCAC A TGGCACAA 3319 Non polyposis CATATATTCGACAAACTGGGGTGATAGTACTCATGGCCCAAAT 3320 colorectal cancer TGGGTGTTTTGTGCCAT G TGAGTCAGCAGAAGTGTCCATTGT Cys697Phe GGACTGCATCTTAGCCCGAGTAGGGGCTGGTGACAG TGT-TTT CTGTCACCAGCCCCTACTCGGGCTAAGATGCAGTCCACAATG 3321 GACACTTCTGCTGACTCA C ATGGCACAAAACACCCAATTTGG GCCATGAGTACTATCACCCCAGTTTGTCGAATATATG TGTGCCAT G TGAGTCAG 3322 CTGACTCA C ATGGCACA 3323 Non polyposis GAGTCAGCAGAAGTGTCCATTGTGGACTGCATCTTAGCCCGA 3324 colorectal cancer GTAGGGGCTGGTGACAGT C AATTGAAAGGAGTCTCCACGTTC Gln718Term ATGGCTGAAATGTTGGAAACTGCTTCTATCCTCAGGT CAA-TAA ACCTGAGGATAGAAGCAGTTTCCAACATTTCAGCCATGAACG 3325 TGGAGACTCCTTTCAATT G ACTGTCACCAGCCCCTACTCGGG CTAAGATGCAGTCCACAATGGACACTTCTGCTGACTC GTGACAGT C AATTGAAA 3326 TTTCAATT G ACTGTCAC 3327 Non polyposis CCAATCAGATACCAACTGTTAATAATCTACATGTCACAGCACT 3328 colorectal cancer CACCACTGAAGAGACCT T AACTATGCTTTATCAGGTGAAGAAA Leu811Term GGTATGTACTATTGGAGTACTCTTAAATTCAGAACT TTA-TGA AGTTCTGAATTTAGAGTACTCCAATAGTACATACCTTTCTTCAC 3329 CTGATTAAAGCATAGTT A AGGTCTCTTCAGTGGTGAGTGCTGT GACATGTAGATTATTAACAGTTGGTATCTGATTGG AGAGACCT T AACTATGC 3330 GCATAGTT A AGGTCTCT 3331 Non polyposis TTCCCCAAATTTCTTATAGGTGTCTGTGATCAAAGTTTTGGGA 3332 colorectal cancer TTCATGTTGCAGAGCTT G CTAATTTCCCTAAGCATGTAATAGA Ala834Thr GTGTGCTAAACAGAAAGCCCTGGAACTTGAGGAGT GCT-ACT ACTCCTCAAGTTCCAGGGCTTTCTGTTTAGCACACTCTATTAC 3333 ATGCTTAGGGAAATTAG C AAGCTCTGCAACATGAATCCCAAAA CTTTGATCACAGACACCTATAAGAAATTTGGGGAA CAGAGCTT G CTAATTTC 3334 GAAATTAG C AAGCTCTG 3335 Non polyposis ATAGAGTGTGCTAAACAGAAAGCCCTGGAACTTGAGGAGTTT 3336 colorectal cancer CAGTATATTGGAGAATCGC A AGGATATGATATCATGGAACCAG Gln861Term CAGCAAAGAAGTGCTATCTGGAAAGAGAGGTTTGTC CAA-TAA GACAAACCTCTCTTTCCAGATAGCACTTCTTTGCTGCTGGTTC 3337 CATGATATCATATCCTT G CGATTCTCCAATATACTGAAACTCCT CAAGTTCCAGGGCTTTCTGTTTAGCACACTCTAT GAGAATCG C AAGGATAT 3338 ATATCCTT G CGATTCTC 3339 Non polyposis AGGAGTTCCTGTCCAAGGTGGAACAAATGCCCTTTACTGAAAT 3340 colorectal cancer GTCAGAAGAAAACATCA C AATAAAGTTAAAACAGCTAAAAGCT Thr905Arg GAAGTAATAGCAAAGAATAATAGCTTTGTAAATGA ACA-AGA TCATTTACAAAGCTATTATTCTTTGCTATTACTTCAGCTTTTAG 3341 CTGTTTTAACTTTATT G TGATGTTTTCTTCTGACATTTCAGTAA AGGGCATTTGTTTCACCTTGGACAGGAACTCCT AAACATCA C AATAAAGT 3342 ACTTTATT G TGATGTTT 3343

EXAMPLE 19 Human Mismatch Repair—MSH6

The human MSH6 gene is homologous to the bacterial mutS gene, which is involved in mismatch repair. Mutations in the MSH6 gene have been identified in a variety of cancers, including particularly hereditary nonpolyposis colorectal cancer. The attached table discloses the correcting oligonucleotide base sequences for the MSH6 oligonucleotides of the invention.

TABLE 26 MSH6 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Non-polyposis GGAAATCAGTCCGTGTTCATGTACAGTTTTTTGATGACAGCCC 3344 colorectal cancer AACAAGGGGCTGGGTTA G CAAAAGGCTTTTAAAGCCATATAC Ser144lle AGGTAAGAGTCACTACTGCCATGTGTGTGTGTTTGT AGC-ATC ACAAACACACACACATGGCAGTAGTGACTCTTACCTGTATATG 3345 GCTTTAAAAGCCTTTTG C TAACCCAGCCCCTTGTTGGGCTGT CATCAAAAAACTGTACATGAACACGGACTGATTTCC CTGGGTTA G CAAAAGGC 3346 GCCTTTTG C TAACCCAG 3347 Endometrial cancer CGTGAGCCTCTGCACCCGGCCCTTATTGTTTATAAATACATTT 3348 Ser156Term CTTTCTAGGTTCAAAAT C AAAGGAAGCCCAGAAGGGAGGTCA TCA-TGA TTTTTACAGTGCAAAGCCTGAAATACTGAGAGCAAT ATTGCTCTCAGTATTTCAGGCTTTGCACTGTAAAAATGACCTC 3349 CCTTCTGGGCTTCCTTT G ATTTTGAACCTAGAAAGAAATGTAT TTATAAACAATAAGGGCCGGGTGCAGAGGCTCACG TTCAAAAT C AAAGGAAG 3350 CTTCCTTT G ATTTTGAA 3351 Early onset colorectal TTCCAAATTTTGATTTGTTTTTAAATACTCTTTCCTTGCCTGGC 3352 cancer AGGTAGGCACAACTTA C GTAACAGATAAGAGTGAAGAAGATA Tyr214Term ATGAAATTGAGAGTGAAGAGGAAGTACAGCCTAAG TAC-TAG CTTAGGCTGTACTTCCTCTTCACTCTCAATTTCATTATCTTCTT 3353 CACTCTTATCTGTTAC G TAAGTTGTGCCTACCTGCCAGGCAA GGAAAGAGTATTTAAAAACAAATCAAAATTTGGAA ACAACTTA C GTAACAGA 3354 TCTGTTAC G TAAGTTGT 3355 Endometrial cancer GAAGAGGAAGTACAGCCTAAGACACAAGGATCTAGGCGAAGT 3356 Arg248Term AGCCGCCAAATAAAAAAA C GAAGGGTCATATCAGATTCTGAG CGA-TGA AGTGACATTGGTGGCTCTGATGTGGAATTTAAGCCAG CTGGCTTAAATTCCACATCAGAGCCACCAATGTCACTCTCAGA 3357 ATCTGATATGACCCTTC G TTTTTTTATTTGGCGGCTACTTCGC CTAGATCCTTGTGTCTTAGGCTGTACTTCCTCTTC TAAAAAAA C GAAGGGGTC 3358 GACCCTTC G TTTTTTTA 3359 Colorectal cancer TTAAGCCAGACACTAAGGAGGAAGGAAGCAGTGATGAAATAA 3360 Ser285lle GCAGTGGAGTGGGGGATA G TGAGAGTGAAGGCCTGAACAGC AGT-ATT CCTGTCAAAGTTGCTCGAAAGCGGAAGAGAATGGTGAC GTCACCATTCTCTTCCGCTTTCGAGCAACTTTGACAGGGCTG 3361 TTCAGGCCTTCACTCTCA C TATCCCCCACTCCACTGCTTATTT CATCACTGCTTCCTTCCTCCTTAGTGTCTGGCTTAA GGGGGATA G TGAGAGTG 3362 CACTCTCA C TATCCCCC 3363 Colorectal cancer GAGGAAGATTCTTCTGGCCATACTCGTGCATATGGTGTGTGC 3364 Gly566Arg TTTGTTGATACTTCACTG G GAAAGTTTTTCATAGGTCAGTTTTC GGA-AGA AGATGATCGCCATTGTTCGAGATTTAGGACTCTAG CTAGAGTCCTAAATCTCGAACJAATGGCGATCATCTGAAAACTG 3365 ACCTATGAAAAACTTTC C CAGTGAAGTATCAACAAAGCACACA CCATATGCACGAGTATGGCCAGAAGAATCTTCCTC CTTCACTG G GAAAGTTT 3366 AAACTTTC C CAGTGAAG 3367 Non-polyposis GAATTGGCCCTCTCTGCTCTAGGTGGTTGTGTCTTCTACCTC 3368 colorectal cancer AAAAAATGCCTTATTGAT C AGGAGCTTTTATCAATGGCTAATTT Gln698Glu TGAAGAATATATTCCCTTGGATTCTGACACAGTCA CAG-GAG TGACTGTGTCAGAATCCAAGGGAATATATTCTTCAAAATTAGC 3369 CATTGATAAAAGCTCCT G ATCAATAAGGCATTTTTTGAGGTAG AAGACACAACCACCTAGAGCAGAGAGGGCCAATTC TTATTGAT C AGGAGCTT 3370 AAGCTCCT G ATCAATAA 3371 Endometrial cancer CCCTTGGATTCTGACACAGTCAGCACTACAAGATCTGGTGCT 3372 Gln731Term ATCTTCACCAAAGCCTAT C AACGAATGGTGCTAGATGCAGTG CAA-TAA ACATTAAACAACTTGGAGATTTTTCTGAATGGAACAA TTGTTCCATTCAGAAAAATCTCCAAGTTGTTTAATGTCACTGCA 3373 TCTAGCACCATTCGTT G ATAGGCTTTGGTGAAGATAGCACCA GATCTTGTAGTGCTGACTGTGTCAGAATCCAAGGG AAGCCTAT C AACGAATG 3374 CATTCGTT G ATAGGCTT 3375 Colorectal cancer GCCCCACTCTGTAACCATTATGCTATTAATGATCGTCTAGATG 3376 Val800Leu CCATAGAAGACCTCATG G TTGTGCCTGACAAAATCTCCGAAG GTT-CTT TTGTAGAGCTTCTAAAGAAGCTTCCAGATCTTGAGA TCTCAAGATCTGGAAGCTTCTTTAGAAGCTCTACAACTTCGGA 3377 GATTTTGTCAGGCACAA C CATGAGGTCTTCTATGGCATCTAGA CGATCATTAATAGCATAATGGTTACAGAGTGGGGC ACCTCATG G TTGTGCCT 3378 AGGCACAA C CATGAGGT 3379 Colorectal cancer GTAACCATTATGCTATTAATGATCGTCTAGATGGCATAGAAGA 3380 Asp803Gly CCTCATGGTTGTGCCTG A CAAAATCTCCGAAGTTGTAGAGCT GAC-GGC TCTAAAGAAGCTTCCAGATCTTGAGAGGCTACTCAG CTGAGTAGCCTCTCAAGATCTGGAAGCTTCTTTAGAAGCTCTA 3381 CAACTTCGGAGATTTTG T CAGGCACAACCATGAGGTCTTCTAT GGCATCTAGACGATCATTAATAGCATAATGGTTAC TGTGCGTG A CAAAATCT 3382 AGATTTTG T CAGGCACA 3383 Non-polyposis CTCCCCTGAAGAGTCAGAACCACCCAGACAGCAGGGCTATAA 3384 colorectal cancer TGTATGAAGAAACTACAT A CAGCAAGAAGAAGATTATTGATTT Tyr850Cys TCTTTCTGCTCTGGAAGGATTCAAAGTAATGTGTAA TAC-TGC TTACACATTACTTTGAATCCTTCCAGAGCAGAAAGAAATCAA 3385 TAATCTTCTTCTTGCTG T ATGTAGTTTCTTCATACATTATAGCC CTGCTGTCTGGGTGGTTCTGACTCTTCAGGGGAG AACTACAT A CAGCAAGA 3386 TCTTGCTG T ATGTAGTT 3387 Colorectal cancer TATAGTCGAGGGGGTGATGGTCCTATGTGTCGCCCAGTAATT 3388 Pro1087Thr CTGTTGCCGGAAGATACC C CCCCCTTCTTAGAGCTTAAAGGA CCC-ACC TCACGCCATCCTTGCATTACGAAGACTTTTTTTGGAG CTCCAAAAAAAGTCTTCGTAATGCAAGGATGGCGTGATCCTTT 3389 AAGCTCTAAGAAGGGGG G GGTATCTTCCGGCAACAGAATTAC TGGGCGACACATAGGACCATCACCCCCTCGACTATA AAGATACC C CCCCCTTC 3390 GAAGGGGG G GGTATCTT 3391 Non-polyposis ACTATAAAATGTCGTACATTATTTFCAACTCACTACCATTCATT 3392 colorectal cancer AGTAGAAGATTATTCT C AAAATGTTGCTGTGCGCCTAGGACAT Gln1258Term ATGGTATGTGCAAATTGTTTTFTTCCACAAATTC CAA-TAA GAATTTGTGGAAAAAAACAATTTGCACATACCATATGTCCTAG 3393 GCGCACAGCAACATTTT G AGAATAATCTTCTACTAATGAATGG TAGTGAGTTGAAAATAATGTACGACATTTTATAGT ATTATTCT C AAAATGTT 3394 AACATTTT G AGAATAAT 3395

EXAMPLE 20 Hyperlipidemia—APOE

Hyperlipidemia is the abnormal elevation of plasma cholesterol and/or triglyceride levels and it is one of the most common diseases. The human apolipoprotein E protein is involved in the transport of endogenous lipids and appears to be crucial for both the direct removal of cholesterol-rich LDL from plasma and conversion of IDL particles to LDL particles. Individuals who either lack apolipoprotein E or who are homozygous for particular alleles of apoE may have have a condition known as dysbetalipoproteinemia, which is characterized by elevated plasma cholesterol and triglyceride levels and an increased risk for atherosclerosis.

In a comprehensive review of apoE variants, de Knijff et al., Hum. Mutat. 4:178-194 (1994) found that 30 variants had been characterized, including the most common variant, apoE3. To that time, 14 apoE variants had been found to be associated with familial dysbetalipoproteinemia. The attached table discloses the correcting oligonucleotide base sequences for the APOE oligonucleotides of the invention.

TABLE 27 APOE Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Apolipoprotein TTGTTCCACACAGGATGCCAGGCCAAGGTGGAGCAAGCGGT 3396 Glu13Lys GGAGACAGAGCCGGAGCCC G AGCTGCGCCAGCAGACCGAG cGAG-AAG TGGCAGAGCGGCCAGCGCTGGGAACTGGCACTGGGTCGCT AGCGACCCAGTGCCAGTTCCCAGCGCTGGCCGCTCTGCCAC 3397 TCGGTCTGCTGGCGCAGCT C GGGCTCCGGCTCTGTCTCCAC CGCTTGCTCCACCHGGCCTGGCATCCTGTGTGGAACAA CGGAGCCC G AGCTGCGC 3398 GCGCAGCT C GGGCTCCG 3399 Apolipoprotein E CAAGGTGGAGCAAGCGGTGGAGACAGAGCCGGAGCCCGAG 3400 Trp20Term CTGCGCCAGCAGACCGAGTG G CAGAGCGGCCAGCGCTGGG TGGc-TGA AACTGGCACTGGGTCGCTTFTGGGATTACCTGCGCTGGGTG CACCCAGCGCAGGTAATCCCAAAAGCGACCCAGTGCCAGTT 3401 CCCAGCGCTGGCCGCTCTG C CACTCGGTCTGCTGGCGCAGC TCGGGCTCCGGCTCTGTCTCCACCGCTTGCTGCACCTTG ACCGAGTG G CAGAGCGG 3402 CCGCTCTGCCACTCGGT 3403 Apolipoprotein E CAGAGCCGGAGCCCGAGCTGCGCCAGCAGACCGAGTGGCA 3404 Leu28Pro GAGCGGCCAGCGCTGGGAAC T GGCACTGGGTCGCTTTTGGG CTG-CCG ATTACCTGCGCTGGGTGCAGACACTGTCTGAGCAGGTGCA TGCACCTGCTCAGACAGTGTCTGCACCCAGCGCAGGTAATCC 3405 CAAAAGCGACCCAGTGCC A GTTCCCAGCGCTGGCCGCTCTG CCACTCGGTGTGCTGGCGCAGCTCGGGCTCCGGCTCTG CTGGGAAC T GGCACTGG 3406 CCAGTGCC A GTTCCCAG 3407 Apolipoprotein E CGGCTGTCCAAGGAGCTGCAGGCGGCGCAGGCCCGGCTGG 3408 Cys112Arg GCGCGGACATGGAGGACGTG T GCGGCCGCCTGGTGCAGTA gTGC-CGC CCGCGGCGAGGTGCAGGCCATGCTCGGCCAGAGCACCGAGG CCTCGGTGCTCTGGCCGAGCATGGCCTGCACCTCGCCGCGG 3409 TACTGCACCAGGCGGCCGC A CACGTCCTCCATGTCCGCGCC CAGCCGGGCCTGCGCCGCCTGCAGCTCCTTGGACAGCCG AGGACGTG T GCGGCCGC 3410 GCGGCCGC A CACGTCCT 3411 Apolipoprotein E ACATGGAGGACGTGTGCGGCCGCCTGGTGCAGTACCGCGG 3412 Gly127Asp CGAGGTGCAGGCCATGCTCG G CCAGAGCACCGAGGAGCTGT GGC-GAC CGGGTGCGCCTCGCCTCCCACCTGCGCAAGCTGCGTAAGCG CGCTTACGCAGCTTGCGCAGGTGGGAGGCGAGGCGCACCC 3413 GCAGCTCCTCGGTGCTCTGG C CGAGCATGGCCTGCACCTCG CCGCGGTACTGCACCAGGCGGCCGCACACGTCCTCCATGT CATGCTCG G CCAGAGCA 3414 TGCTCTGG C CGAGCATG 3415 Apolipoprotein E GTGCAGTACCGCGGCGAGGTGCAGGCCATGCTCGGCCAGA 3416 Arg136Cys GCACCGAGGAGCTGCGGGTG C GCCTCGCCTCCCACCTGCG gCGC-TGC CAAGCTGCGTAAGCGGCTCCTCCGCGATGCCGATGACCTGC GCAGGTCATGGGCATCGCGGAGGAGCCGCTTACGCAGCTTG 3417 CGCAGGTGGGAGGCGAGGC G CACCCGCAGCTCCTCGGTGC TCTGGCCGAGCATGGCCTGCACCTCGCCGCGGTACTGCAC TGCGGGTG C GCCTCGCC 3418 GGCGAGGC G CACCCGCA 3419 Apolipoprotein E TGCAGTACCGCGGCGAGGTGCAGGCCATGCTCGGCCAGAG 3420 Arg136His CACCGAGGAGCTGCGGGTGC G CCTCGCCTCCCACCTGCGC CGC-CAC AAGCTGCGTAAGCGGCTCCTCCGCGATGCCGATGACCTGCA TGCAGGTCATCGGCATCGCGGAGGAGCCGCTTACGCAGCTT 3421 GCGCAGGTGGGAGGCGAGG C GCACCCGCAGCTCCTCGGTG CTCTGGCCGAGCATGGCCTGCACCTCGCCGCGGTACTGCA GCGGGTGC G CCTCGCCT 3422 AGGCGAGG C GCACCCGC 3423 Apolipoprotein E GTGCAGTACCGCGGCGAGGTGCAGGCCATGCTCGGCCAGA 3424 Arg136Ser GCACCGAGGAGCTGCGGGTG C GCCTCGCCTCGCACCTGCG gCGC-AGC CAAGCTGCGTAAGCGGCTCCTCCGCGATGCCGATGACCTGC GCAGGTCATCGGCATCGCGGAGGAGCCGCTTACGCAGTTG 3425 CGCAGGTGGGAGGCGAGGC G CACCCGCAGCTCCTCGGTGC TCTGGCCGAGCATGGCCTGCACCTCGCCGCGGTACTGCAC TGCGGGTG C GCCTCGCC 3426 GGCGAGGC G CACCCGCA 3427 Apolipoprotein E GTGCAGGCCATGCTCGGCCAGAGCACCGAGGAGCTGCGGG 3428 Arg142Cys TGCGCCTCGCCTCCCACCTG C GCAAGCTGCGTAAGCGGCTC gCGC-TGC CTCCGCGATGCCGATGACCTGCAGAAGCGCCTGGCAGTGT ACACTGCCAGGCGCTTCTGCAGGTCATCGGCATCGCGGAGG 3429 AGCCGCTTACGCAGCTTGC G CAGGTGGGAGGCGAGGCGCA CCCGCAGCTCCTCGGTGCTCTGGCCGAGCATGGCCTGCAC CCCACCTG C GCAAGCTG 3430 CAGCTTGC G CAGGTGGG 3431 Apolipoprotein E TGCAGGCCATGCTCGGCCAGAGCACCGAGGAGCTGCGGGT 3432 Arg142Leu GCGCCTCGCCTCCCACCTGC G CAAGCTGCGTAAGCGGCTCC CGC-CTC TCCGCGATGCCGATGACCTGCAGAAGCGCCTGGCAGTGTA TACACTGCCAGGCGCTTCTGCAGGTCATCGGCATCGCGGAG 3433 GAGCCGCTTACGCAGCTTG C GCAGGTGGGAGGCGAGGCGC ACCCGCAGCTCCTCGGTGCTCTGGCCGAGCATGGCCTGCA CCACCTGC G CAAGCTGC 3434 GCAGCTTG C GCAGGTGG 3435 Apolipoprotein E ATGCTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCG 3436 Arg145Cys CCTCCCACCTGCGCAAGCTG C GTAAGCGGCTCCTCCGCGAT gCGT-TGT GCCGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCG CGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCGGCA 3437 TCGCGGAGGAGCCGCTTAC G CAGCTTGCGCAGGTGGGAGG CGAGGCGCACCCGCAGGTCCTCGGTGCTCTGGCCGAGCAT GCAAGCTG C GTAAGCGG 3438 CCGCTTAC G CAGCTTGC 3439 Apolipoprotein E TGCTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCGC 3440 Arg145Pro CTCCCACCTGCGCAAGCTGC G TAAGCGGCTCCTCCGCGATG CGT-CCT CCGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCGG CCGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCGGC 3441 ATCGCGGAGGAGCCGCTTA C GCAGCTTGCGCAGGTGGGAG GCGAGGCGCACCCGCAGCTCCTCGGTGCTCTGGCCGAGCA CAAGCTGC G TAAGCGGC 3442 GCCGCTTA C GCAGCTTG 3443 Apolipoprotein E CTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCGCCT 3444 Lys146Gln CCCACCTGCGCAAGCTGCGT A AGCGGCTCCTCCGCGATGCC tAAG-CAG GATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCGGGG CCCCGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCG 3445 GCATCGCGGAGGAGCCGCT T ACGCAGCTTGCGCAGGTGGGA GGCGAGGCGCACCCGCAGCTCCTCGGTGCTGTGGCCGAG AGCTGCGT A AGCGGCTC 3446 GAGCCGCT T ACGCAGCT 3447 Apolipoprotein E CTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCGCCT 3448 Lys146Glu CCCACCTGCGCAAGCTGCGT A AGCGGCTCCTCCGCGATGCC tAAG-GAG GATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCGGGG CCCCGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCG 3449 GCATCGCGGAGGAGCCGCT T ACGCAGCTTGCGCAGGTGGGA GGCGAGGCGCACCCGCAGCTCCTCGGTGCTCTGGCCGAG AGCTGCGT A AGCGGCTC 3450 GAGCCGCT T ACGCAGCT 3451 Apolipoprotein E GCCTCCCACCTGCGCAAGCTGCGTAAGCGGCTCCTCCGCGA 3452 Arg158Cys TGCCGATGACCTGCAGAAG C GCCTGGCAGTGTACCAGGCCG gCGC-TGC GGGCCCGCGAGGGCGCCGAGCGCGGCCTCAGCGCCATCC GGATGGCGCTGAGGCCGCGCTCGGCGCCCTCGCGGGCCCC 3453 GGCCTGGTACACTGCCAGGC G CTTCTGCAGGTCATCGGCAT CGCGGAGGAGCCGCTTACGCAGCTTGCGCAGGTGGGAGGC TGCAGAAG C GCCTGGCA 3454 TGCCAGGC G CTTCTGCA 3455 Apolipoprotein E CGCGAGGGCGCCGAGCGCGGCCTCAGCGCCATCCGCGAGC 3456 Gln187Glu GCCTGGGGCCCCTGGTGGAA C AGGGCCGCGTGCGGGCCGC aCAG-GAG CACTGTGGGCTCCCTGGCCGGCCAGCCGCTACAGGAGCGGG CCCGCTCCTGTAGCGGCTGGCCGGCCAGGGAGCCCACAGT 3457 GGCGGCCCGCACGCGGCCCT G TTCCACCAGGGGCCCCAGG CGCTCGCGGATGGCGCTGAGGCCGCGCTCGGCGCCCTCGCG TGGTGGAA C AGGGCCGC 3458 GCGGCCCT G TTCCACCA 3459 Apolipoprotein E TGCGGGCCGCCACTGTGGGCTCCCTGGCCGGCCAGCCGCT 3460 Trp210Term ACAGGAGCGGGCCCAGGCCT G GGGCGAGCGGCTGCGCGC TGG-TAG GCGGATGGAGGAGATGGGCAGCCGGACCCGCGACCGCCTGGA TCCAGGCGGTCGCGGGTCCGGCTGCCCATCTCCTCCATCCG 3461 CGCGCGCAGCCGCTCGCCC C AGGCCTGGGCCCGCTCCTGT AGCGGCTGGCCGGCCAGGGAGCCCACAGTGGCGGCCCGCA CCAGGCCT G GGGCGAGC 3462 GCTCGCCC C AGGCCTGG 3463 Apolipoprotein E CAGGCCTGGGGCGAGCGGCTGCGCGCGCGGATGGAGGAGA 3464 Arg228Cys TGGGCAGCCGGACCCGCGAC C GCCTGGACGAGGTGAAGGA cCGC-TGC GCAGGTGGCGGAGGTGCGCGCCAAGCTGGAGGAGCAGGCCC GGGCCTGCTCCTCCAGCTTGGCGCGCACCTCCGCCACCTGC 3465 TCCTTCACCTCGTCCAGGC G GTCGCGGGTCCGGCTGCCCAT CTCCTCCATCCGCGCGCGCAGCCGCTCGCCCCAGGCCTG CCCGCGAC C GCCTGGAC 3466 GTCCAGGC G GTCGCGGG 3467 Apolipoprotein E CGGACCCGCGACCGCCTGGACGAGGTGAAGGAGCAGGTGG 3468 Glu244Lys CGGAGGTGCGCGCCAAGCTG G AGGAGCAGGCCCAGCAGAT gGAG-AAG ACGCCTGCAGGCCGAGGCCTTCCAGGCCCGCCTCAAGAGCT AGCTCTTGAGGCGGGCCTGGAAGGCCTCGGCCTGGAGGCGT 3469 ATCTGCTGGGCCTGCTCCT C CAGCTTGGCGCGCACCTCCGC CACCTGCTCCTTCACCTCGTCCAGGCGGTCGCGGGTCCG CCAAGCTG G AGGAGCAG 3470 CTGCTCCT C CAGCTTGG 3471

EXAMPLE 21 Familial Hypercholesterolemia—LDLR

Familial hypercholesterolemia is characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL) and is, hence, one of the conditions producing a hyperlipoproteinemia phenotype. Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL). Mutations in the LDL receptor (LDLR) gene cause this disorder. The attached table discloses the correcting oligonucleotide base sequences for the LDLR oligonucleotides of the invention.

TABLE 28 LDLR Mutations and Genome-Correcting Oligos Cilnical Phenotype & SEQ ID Mutation Correcting Oligos NO: Hypercholesterolaemia GCGTTGAGAGACCCTTTCTCCTTTTCCTCTCTCTCAGTGGGC 3472 Glu10Term GACAGATGCGAAAGAAAC G AGTTCCAGTGCCAAGACGGGAA cGAG-TAG ATGCATCTCCTACAAGTGGGTCTGCGATGGCAGCGCTG CAGCGCTGCCATCGCAGACCCACTTGTAGGAGATGCATTTCC 3473 CGTCTTGGCACTGGAACT C GTTTCTTTCGCATCTGTCGCCCA CTGAGAGAGAGGAAAAGGAGAAAGGGTCTCTCAACGC AAAGAAAC G AGTTCCAG 3474 CTGGAACT C GTTTCTTT 3475 Hypercholesterolaemia AGAGACCCTTTCTCCTTTTCCTCTCTCTCAGTGGGCGACAGA 3476 Gln12Term TGCGAAAGAAACGAGTT C CAGTGCCAAGACGGGAAATGCATC cCAG-TAG TCCTACAAGTGGGTCTGCGATGGCAGCGCTGAGTGCC GGCACTCAGCGCTGCCATCGCAGACCCACTTGTAGGAGATG 3477 CATTTCCCGTCTTGGCACT G GAAGTCGTTTCTTTCGCATCTGT CGCCCACTGAGAGAGAGGAAAAGGAGAAAGGGTCTCT ACGAGTTC C AGTGCCAA 3478 TTGGCACT G GAACTCGT 3479 Hyperchoiesterolaemia CCTTTCTCCTTTTCCTCTCTCTCAGTGGGCGACAGATGCGAA 3480 Gln14Term AGAAACGAGTTCCAGTGC C AAGACGGGAAATGCATCTCCTAC cCAA-TAA AAGTGGGTCTGCGATGGCAGCGCTGAGTGCCAGGATG CATCCTGGCACTCAGCGCTGCCATCGCAGACCCACTTGTAG 3481 GAGATGCATTTCCCGTCTT G GCACTGGAACT CATCTGTCGCCCACTGAGAGAGAGGAAAAGGAGAAAGG TCCAGTGC C AAGACGGG 3482 CCCGTCTT G GCACTGGA 3483 Hypercholesterolaemia GCGACAGATGCGAAAGAAACGAGTTCCAGTGCCAAGACGGG 3484 Trp23Term AAATGCATCTCCTACAAGT G GGTCTGCGATGGCAGCGCTGAG TGG-TAG TGCCAGGATGGCTCTGATGAGTCCCAGGAGACGTGCTG CAGCACGTCTCCTGGGACTCATCAGAGCCATCCTGGCACTCA 3485 GCGCTGCCATCGCAGACC C ACTTGTAGGAGATGCATTTCCCG TCTTGGCACTGGAACTCGTTTCTTTCGCATCTGTCGC CTACAAGT G GGTCTGCG 3486 CGCAGACC C ACTTGTAG 3487 Hypercholesterolaemia AACGAGTTCCAGTGCCAAGACGGGAAATGCATCTCCTACAAG 3488 Ala29Ser TGGGTCTGCGATGGCAGC G CTGAGTGCCAGGATGGCTCTGA cGCT-TCT TGAGTCCCAGGAGACGTGCTGTGAGTCCCCTTTGGGCA TGCCCAAAGGGGACTCACAGCACGTCTCCTGGGACTCATCA 3489 GAGCCATCCTGGCACTCAG C GCTGCCATCGCAGACCCACTT GTAGGAGATGCATTTCCCGTCTTGGCACTGGAACTCGTT ATGGCAGC G CTGAGTGC 3490 GCACTCAG C GCTGCCAT 3491 Hypercholesterolaemia TCCAGTGCCAAGACGGGAAATGCATCTCCTACAAGTGGGTCT 3492 Cys31Tyr GCGATGGCAGCGCTGAGT G CCAGGATGGCTCTGATGAGTCC TGC-TAC CAGGAGACGTGCTGTGAGTCCCCTTTGGGCATGATATG CATATCATGCCCAAAGGGGACTCACAGCACGTCTCCTGGGAC 3493 TCATCAGAGCCATCCTGGCACTCAGCGCTGCCATCGCAGAC CCACTTGTAGGAGATGCATTTCCCGTCTTGGCACTGGA CGCTGAGT G CCAGGATG 3494 CATCCTGG C ACTCAGCG 3495 Hypercholesterolaemia AATCCTGTCTCTTCTGTAGTGTCTGTCACCTGCAAATCCGGG 3496 Arg57Cys GACTTCAGCTGTGGGGGC C GTGTCAACCGCTGCATTCCTCA cCGT-TGT GTTCTGGAGGTGCGATGGCCAAGTGGACTGCGACAACG CGTTGTCGCAGTCCACTTGGCCATCGCACCTCCAGAACTGAG 3497 GAATGCAGCGGTTGACAC G GCCCCCACAGCTGAAGTCCCCG GATTTGCAGGTGACAGACACTACAGAAGAGACAGGATT GTGGGGGC C GTGTCAAC 3498 GTTGACAC G GCCCCCAC 3499 Hypercholesterolaemia TCTGTCACCTGCAAATCCGGGGACTTCAGCTGTGGGGGCCG 3500 Gln64Term TGTCAACCGCTGCATTCCT C AGTTCTGGAGGTGCGATGGCCA tCAG-TAG AGTGGACTGCGACAACGGCTCAGACGAGCAAGGCTGTC GACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCCACTTGGC 3501 CATCGCACCTCCAGAACT G AGGAATGCAGCGGTTGACACGG CCCCCACAGCTGAAGTCCCCGGATTTGCAGGTGACAGA GCATTCCT C AGTTCTGG 3502 CCAGAACT G AGGAATGC 3503 Hypercholesterolaemia ACCTGCAAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAA 3504 Trp66Gly CCGCTGCATTCCTCAGTTC T GGAGGTGCGATGGCCAAGTGG cTGG-GGG ACTGCGACAACGGCTCAGACGAGCAAGGCTGTCGTAAGT ACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCCA 3505 CTTGGCCATCGCACCTCC A GAACTGAGGAATGCAGCGGTTG ACACGGCCCCCACAGCTGAAGTCCCCGGATTTGCAGGT CTCAGTTC T GGAGGTGC 3506 GCACCTCC A GAACTGAG 3507 Hypercholesterolaemia CCTGCAAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAAC 3508 Trp66Term CGCTGCATTCCTCAGTTCT G GAGGTGCGATGGCCAAGTGGA TGG-TAG CTGCGACAACGGCTCAGACGAGCAAGGCTGTCGTAAGTG CACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCC 3509 ACTTGGCCATCGCACCTC C AGAACTGAGGAATGCAGCGGTG ACACGGCCCCCACAGCTGAAGTCCCCGGATTTGCAGG TCAGTTCT G GAGGTGCG 3510 CGCACCTC C AGAACTGA 3511 Hypercholesterolaemia AAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTG 3512 Cys68Arg CATTCCTCAGTTCTGGAGG T GCGATGGCCAAGTGGACTGCGA gTGC-CGC CAACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCC GGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGC 3513 AGTCCACTTGGCCATCGC A CCTCCAGAACTGAGGAATGCAG CGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGATTT TCTGGAGG T GCGATGGC 3514 GCCATCGC A CCTCCAGA 3515 Hypercholesterolaemia ATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCA 3516 Cys68Trp TTCCTCAGTTCTGGAGGTG C GATGGCCAAGTGGACTGCGACA TGCg-TGG ACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCT AGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTC 3517 GCAGTCCACTTGGCCATC G CACCTCCAGAACTGAGGAATGCA GCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGAT TGGAGGTG C GATGGCCA 3518 TGGCCATC G CACCTCCA 3519 Hypercholesterolaemia AATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGC 3520 Cys68Tyr ATTCCTCAGTTCTGGAGGT G CGATGGCCAAGTGGACTGCGAC TGC-TAC AACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCC GGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTC 3521 GCAGTCCACTTGGCCATCG C ACCTCCAGAACTGAGGAATGCA GCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGATT CTGGAGGT G CGATGGCC 3522 GGCCATCG C ACCTCCAG 3523 Hypercholesterolaemia TCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCAT 3524 Asp69Asn TCCTCAGTTCTGGAGGTGC G ATGGCCAAGTGGACTGCGACA cGAT-AAT ACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTG CAGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGT 3525 CGCAGTCCACTTGGCCAT C GCACCTCCAGAACTGAGGAATG CAGCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGA GGAGGTGC G ATGGCCAA 3526 TTGGCCAT C GCACCTCC 3527 Hypercholesterolaemia CCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCATT 3528 Asp69Gly CCTCAGTTCTGGAGGTGCG A TGGCCAAGTGGACTGCGACAA GAT-GGT CGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTGC GCAGGGCCACACTTACGACAGCCTTGGTCGTCTGAGCCGTT 3529 GTCGCAGTCCACTTGGCCA T CGCACCTCCAGAACTGAGGAAT GCAGCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGG GAGGTGCG A TGGCCAAG 3530 CTTGGCCA T CGCACCTC 3531 Hypercholesterolaemia TCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCAT 3532 Asp69Tyr TCCTCAGTTCTGGAGGTGC G ATGGCCAAGTGGACTGCGACA cGAT-TAT ACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTG CAGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGT 3533 CGCAGTCCACTTGGCCAT C GCACCTCCAGAACTGAGGAATG CAGCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGA GGAGGTGC G ATGGCCAA 3534 TTGGCCAT C GCACCTCC 3535 Hypercholesterolaemia GACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCATTCCTCA 3536 Gln71Glu GTTCTGGAGGTGCGATGGC C AAGTGGACTGCGACAACGGCT cCAA-GAA CAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTGCCTTTG CAAAGGCAGGGCCACACTTACGACAGCCTTGCTCGTCTGAG 3537 CCGTTGTCGCAGTCCACTT G GCCATCGCACCTCCAGAACTGA GGAATGCAGCGGTTGACACGGCCCCCACAGCTGAAGTC GCGATGGC C AAGTGGAC 3538 GTCCACTT G GCCATCGC 3539 Hypercholesterolaemia TGTGGGGGCCGTGTCAACCGCTGCATTCCTCAGTTCTGGAG 3540 Cys74Gly GTGCGATGGCCAAGTGGAC T GCGACAACGGCTCAGACGAGC cTGC-GGC AAGGCTGTCGTAAGTGTGGCCCTGCCTTTGCTATTGAGC GCTCAATAGCAAAGGCAGGGCCACACTTACGACAGCCTTGCT 3541 CGTCTGAGCCGTTGTCGC A GTCCACTTGGCCATCGCACCTC CAGAACTGAGGAATGCAGCGGTTGACACGGCCCCCACA AAGTGGAC T GCGACAAC 3542 GTTGTCGC A GTCCACTT 3543 Hypercholesterolaemia TCAACCGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAG 3544 Ser78Term TGGACTGCGACAACGGCT C AGACGAGCAAGGCTGTCGTAAG TCA-TGA TGTGGCCCTGCGTTTGCTATTGAGCCTATCTGAGTCCT AGGACTCAGATAGGCTCAATAGCAAAGGCAGGGCCACACTTA 3545 CGACAGCCTTGCTCGTCT G AGCCGTTGTCGCAGTCCACTTGG CCATCGCACCTCCAGAACTGAGGAATGCAGCGGTTGA CAACGGCT C AGACGAGC 3546 GCTCGTCT G AGCCGTTG 3547 Hypercholesterolaemia CGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGA 3548 Glu80Lys CTGCGACAACGGCTCAGAC G AGCAAGGCTGTCGTAAGTGTG cGAG-AAG GCCCTGCCTTTGCTATTGAGCCTATCTGAGTCCTGGGGA TCCCCAGGACTCAGATAGGCTCAATAGCAAAGGCAGGGCCA 3549 CACTTACGACAGCCTTGCT C GTCTGAGCCGTTGTCGCAGTCC ACTTGGCCATCGCACCTCCAGAACTGAGGAATGCAGCG GCTCAGAC G AGCAAGGC 3550 GCCTTGCT C GTCTGAGC 3551 Hypercholesterolaemia CGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGA 3552 GTu80Term CTGCGACAACGGCTCAGAC G AGCAAGGCTGTCGTAAGTGTG cGAG-TAG GCCCTGCCTTTGCTATTGAGCCTATCTGAGTCCTGGGGA TCCCCAGGACTCAGATAGGCTCAATAGCAAAGGCAGGGCCA 3553 CACTTACGACAGCCTTGCT C GTCTGAGCCGTTGTCGCAGTCC ACTTGGCCATCGCACCTCCAGAACTGAGGAATGCAGCG GCTCAGAC G AGCAAGGC 3554 GCCTTG C TCGTCTGAGC 3555 Hypercholesterolaemia TGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGACTGC 3556 Gln81Term GACAACGGCTCAGACGAG C AAGGCTGTCGTAAGTGTGGCCC gCAA-TAA TGCCTTTGCTATTGAGCCTATCTGAGTCCTGGGGAGTG CACTCCCCAGGACTCAGATAGGCTCAATAGCAAAGGCAGGG 3557 CCACACTTACGACAGCCTT G CTCGTCTGAGCCGTTGTCGCAG TCCACTTGGCCATCGCACCTCCAGAACTGAGGAATGCA CAGACGAG C AAGGCTGT 3558 ACAGCCTT G CTCGTCTG 3559 Hypercholesterolaemia TGGGAGACTTCACACGGTGATGGTGGTCTCGGCCCATCCAT 3560 Cys88Arg CCCTGCAGCCCCCAAGACG T GCTCCCAGGACGAGTTTCGCT gTGC-CGC GCCACGATGGGAAGTGCATCTCTCGGCAGTTCGTCTGTG CACAGACGAACTGCCGAGAGATGCAGTTCCCATCGTGGCAG 3561 CGAAACTCGTCCTGGGAGC A CGTCTTGGGGGCTGCAGGGAT GGATGGGCCGAGACCACCATCACCGTGTGAAGTCTCCCA CCAAGACG T GCTCCCAG 3562 CTGGGAGC A CGTCTTGG 3563 Hypercholesterolaemia CACGGTGATGGTGGTCTCGGCCCATCCATCCCTGCAGCCCC 3564 Glu92Term CAAGACGTGCTCCCAGGAC G AGTTTCGCTGCCACGATGGGA cGAG-TAG AGTGCATCTCTCGGCAGTTCGTCTGTGACTCAGACCGGG CCCGGTCTGAGTCACAGACGAACTGCCGAGAGATGCACTTC 3565 CCATCGTGGCAGCGTAAACT C GTCCTGGGAGCACGTCTTGGG GGCTGCAGGGATGGATGGGCCGAGACCACCATCACCGTG CCCAGGAC G AGTTFCGC 3566 GCGAAACT C GTCCTGGG 3567 Hypercholesterolaemia GGTGGTCTCGGCCCATCCATCCCTGCAGCCCCCAAGACGTG 3568 Cys95Arg CTCCCAGGACGAGTTTCGC T GCCACGATGGGAAGTGCATCT cTGC-CGC CTCGGCAGTTCGTCTGTGACTCAGACCGGGACTGCTTGG CCAAGCAGTCCCGGTCTGAGTCACAGACGAACTGCCGAGAG 3569 ATGCACTTCCCATCGTGGC A GCGAAACTCGTCCTGGGAGCA CGTCTTGGGGGCTGCAGGGATGGATGGGCCGAGACCACC AGTTTCGC T GCCACGAT 3570 ATCGTGGC A GCGAAACT 3571 Hypercholesterolaemia CTCGGCCCATCCATCCCTGCAGCCCCCAAGACGTGCTCCCA 3572 Asp91Tyr GGACGAGTTTCGCTGCCAC G ATGGGAAGTGCATCTCTCGGC cGAT-TAT AGTTCGTCTGTGACTCAGACCGGGACTGCTTGGACGGCT AGCCGTCCAAGCAGTCCCGGTCTGAGTCACAGACGAACTGC 3573 CGAGAGATGCACTTCCCAT C GTGGCAGCGAAACTCGTCCTG GGAGCACGTCTTGGGGGCTGCAGGGATGGATGGGCCGAG GCTGCCAC G ATGGGAAG 3574 CTTCCCAT C GTGGCAGC 3575 Hypercholesterolaemia GGGTCGGGACACTGCCTGGCAGAGGCTGCGAGCATGGGGC 3576 Trp(−12)Arg CCTGGGGCTGGAAATTGCGC T GGACCGTCGCCTTGCTCCTC cTGG-AGG GCCGCGGCGGGGACTGCAGGTAAGGCTTGCTCCAGGCGCC GGCGCCTGGAGCAAGCCTTACCTGCAGTCCCCGCCGCGGC 3577 GAGGAGCAAGGCGACGGTCC A GCGCAATTCCAGCCCCAGG GCCCCATGCTCGCAGCCTCTGCCAGGCAGTGTCCCGACCC AATTGCGC T GGACCGTC 3578 GACGGTCC A GCGCAATT 3579 Hypercholesterolaemia CAGCAGGTCGTGATCCGGGTCGGGACACTGCCTGGCAGAGG 3580 Trp(−18)Term CTGCGAGCATGGGGCCCTG G GGCTGGAAATTGCGCTGGACC TGGg-TGA GTCGCCTTGCTCCTCGCCGCGGCGGGGACTGCAGGTAAG CTTACCTGCAGTCCCCGCCGCGGCGAGGAGCAAGGCGACG 3581 GTCCAGCGCAATTTCCAGCC C CAGGGCCCCATGCTCGCAGC CTCTGCCAGGCAGTGTCCCGACCCGGATCACGACCTGCTG GGGCCCTG G GGCTGGAA 3582 TTCCAGCC C CAGGGCCC 3583 Hypercholesterolaemia CAGCTAGGACACAGCAGGTCGTGATCCGGGTCGGGACACTG 3584 Met(−21)Leu CCTGGCAGAGGCTGCGAGC A TGGGGCCCTGGGGCTGG cATG-TTG TTGCGCTGGACCGTCGCCTTGCTCCTCGCCGCGGCGGGGA TCCCCGCCGCGGCGAGGAGCAAGGCGACGGTCCAGCGCAA 3585 TTTCCAGCCCCAGGGCCCCA T GCTCGCAGCCTCTGCCAGGC AGTGTGCCGACCCGGATCACGACCTGCTGTGTCCTAGCTG CTGCGAGC A TGGGGCCC 3586 GGGCCCCA T GCTCGCAG 3587 Hypercholesterolaemia CAGCTAGGACACAGCAGGTCGTGATCCGGGTCGGGACACTG 3588 Met(−21 )Val CCTGGCAGAGGCTGCGAGC A TGGGGCCCTGGGGCTGG cATG-GTG TTGCGCTGGACCGTCGCCTTGCTCCTCGCCGCGGCGGGGA TCCCCGCCGCGGCGAGGAGCAAGGCGACGGTCCAGCGCAA 3589 TTTCCAGCCCCAGGGCCCCA T GCTCGCAGCCTCTGCCAGGC AGTGTCCCGACCCGGATCACGACCTGCTGTGTCCTAGCTG CTGCGAGC A TGGGGCCC 3590 GGGCCCCA T GCTCGCAG 3591 Hypercholesterolaemia ATCCCTGCAGCCCCCAAGACGTGCTCCCAGGACGAGTTTCG 3592 lle101Phe CTGCCACGATGGGAAGTGC A TCTCTCGGCAGTTCGTCTGTGA cATC-TTC CTCAGACCGGGACTGCTTGGACGGCTCAGACGAGGCCT AGGCCTCGTCTGAGCCGTCCAAGCAGTCCCGGTCTGAGTCA 3593 CAGACGAACTGCCGAGAGA T GCACTTCCCATCGTGGCAGCG AAACTCGTCCTGGGAGCACGTCTTGGGGGCTGCAGGGAT GGAAGTGC A TCTCTCGG 3594 CCGAGAGA T GCACTTCC 3595 Hypercholesterolaemia GCCCCCAAGACGTGCTCCCAGGACGAGTTTCGCTGCCACGA 3596 Gln104Term TGGGAAGTGCATCTCTCGG C AGTTCGTCTGTGACTCAGACCG gCAG-TAG GGACTGCTTGGACGGCTCAGACGAGGCCTCCTGCCCGG CCGGGCAGGAGGCCTCGTCTGAGCCGTCCAAGCAGTCCCG 3597 GTCTGAGTCACAGACGAACT G CCGAGAGATGCACTTCCCATC GTGGCAGCGAAACTCGTCCTGGGAGCACGTCTTGGGGGC TCTCTCGG C AGTTCGTC 3598 GACGAACT G CCGAGAGA 3599 Hypercholesterolaemia TTFCGCTGCCACGATGGGAAGTGCATCTCTCGGCAGTTCGTC 3600 Cys113Arg TGTGACTCAGACCGGGAC T GCTTGGACGGCTCAGACGAGGC cTGC-CGC CTCCTGCCCGGTGCTCACCTGTGGTCCCGCCAGCTTCC GGAAGCTGGCGGGACCACAGGTGAGCACCGGGCAGGAGGC 3601 CTCGTCTGAGCCGTCCAAGC A GTCCCGGTCTGAGTCACAGA CGAACTGCCGAGAGATGCACTTCCCATCGTGGCAGCGAAA ACCGGGAC T GCTTGGAC 3602 GTCCAAGC A GTCCCGGT 3603 Hypercholesterolaemia AAGTGCATCTCTCGGCAGTTCGTCTGTGACTCAGACCGGGAC 3604 Glu119Lys TGCTTGGACGGCTCAGAC G AGGCCTCCTGCCCGGTGCTCAC cGAG-AAG CTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCT AGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACAGGTG 3605 AGCACCGGGCAGGAGGCCT C GTCTGAGCCGTCCATTAGCAGTC CCGGTCTGAGTCACAGACGAACTGCCGAGAGATGCACTT GCTCAGAC G AGGCCTCC 3606 GGAGGCCT C GTCTGAGC 3607 Hypercholesterolaemia AAGTGCATCTCTCGGCAGTTCGTCTGTGACTCAGACCGGGAC 3608 Glu119Term TGCTTGGACGGCTCAGAC G AGGCCTCCTGCCCGGTGCTCAC cGAG-TAG CTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCT AGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACAGGTG 3609 AGCACCGGGCAGGAGGCCT C GTCTGAGCCGTCCAAGCAGTC CCGGTCTGAGTCACAGACGAACTGCCGAGAGATGCACTT GCTCAGAC G AGGCCTCC 3610 GGAGGCCT C GTCTGAGC 3611 Hypercholesterolaemia TCGGCAGTTCGTCTGTGACTCAGACCGGGACTGCTTGGACG 3612 Cys122Term GCTCAGACGAGGCCTCCTG C CCGGTGCTCACCTGTGGTCCC TGCc-TGA GCCAGCTFCCAGTGCAACAGCTCCACCTGCATCCCCCAG CTGGGGGATGCAGGTGGAGCTGTTGCACTGGAAGCTGGCGG 3613 GACCACAGGTGAGCACCGG G CAGGAGGCCTCGTCTGAGCC GTCCAAGCAGTCCCGGTCTGAGTCACAGACGAACTGCCGA GCCTCCTG C CCGGTGCT 3614 AGCACCGG G CAGGAGGC 3615 Hypercholesterolaemia TGACTCAGACCGGGACTGCTTGGACGGCTCAGACGAGGCCT 3616 Cys127Trp CCTGCCCGGTGCTCACCTG T GGTCCCGCCAGCTTCCAGTGC TGTg-TGG AACAGCTCCACCTGCATCCCCCAGCTGTGGGCCTGCGAC GTCGCAGGCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGC 3617 ACTGGAAGCTGGCGGGACC A CAGGTGAGCACCGGGCAGGA GGCCTCGTCTGAGCCGTCCAAGCAGTCCCGGTCTGAGTCA CTCACCTG T GGTCCCGC 3618 GCGGGACC A CAGGTGAG 3619 Hypercholesterolaemia TGCTTGGACGGCTCAGACGAGGCCTCCTGCCCGGTGCTCAC 3620 Gln133Term CTGTGGTCCCGCCAGCTTC C AGTGCAACAGCTCCACCTGCAT cCAG-TAG CCCCCAGCTGTGGGCCTGCGACAACGACCCCGACTGCG CGCAGTCGGGGTCGTTGTCGCAGGCCCACAGCTGGGGGAT 3621 GCAGGTGGAGCTGTTGCACT G GAAGCTGGCGGGACCACAGG TGAGCACCGGGCAGGAGGCCTCGTCTGAGCCGTCCAAGCA CCAGCTTC C AGTGCAAC 3622 GTTGCACT G GAAGCTGG 3623 Hypercholesterolaemia TTGGACGGCTCAGACGAGGCCTCCTGCCCGGTGCTCACCTG 3624 Cys134Gly TGGTCCCGCCAGCTTCCAG T GCAACAGCTCCACCTGCATCC gTGC-GGC CCCAGCTGTGGGCCTGCGACAACGACCCCGACTGCGAAG CTTCGCAGTCGGGGTCGTTGTCGCAGGCCCACAGCTGGGGG 3625 ATGCAGGTGGAGCTGTTGC A CTGGAAGCTGGCGGGACCACA GGTGAGCACCGGGCAGGAGGCCTCGTCTGAGCCGTCCAA GCTTCCAG T GCAACAGC 3626 GCTGTTGC A CTGGAAGC 3627 Hypercholesterolaemia GAGGCCTCCTGCCCGGTGCTCACCTGTGGTCCCGCCAGCTT 3628 Cys139Gly CCAGTGCAACAGCTCCACC T GCATCCCCCAGCTGTGGGCCT cTGC-GGC GCGACAACGACCCCGACTGCGAAGATGGCTCGGATGAGT ACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTTGTCGCAG 3629 GCCCACAGCTGGGGGATGC A GGTGGAGCTGTTGCACTGGAA GCTGGCGGGACCACAGGTGAGCACCGGGCAGGAGGCCTC GCTCCACC T GCATCCCC 3630 GGGGATGC A GGTGGAGC 3631 Hypercholesterolaemia AGGCCTCCTGCCCGGTGCTCACCTGTGGTCCCGCCAGCTTC 3632 Cys139Tyr CAGTGCAACAGCTCCACCT G CATCCCCCAGCTGTGGGCCTG TGC-TAC CGACAACGACCCCGACTGCGAAGATGGCTCGGATGAGTG CACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTTGTCGCA 3633 GGCCCACAGCTGGGGGATG C AGGTGGAGCTGTTGCACTGGA AGCTGGCGGGACCACAGGTGAGCACCGGGCAGGAGGCCT CTCCACCT G CATCCCCC 3634 GGGGGATG C AGGTGGAG 3635 Hypercholesterolaemia CTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCAT 3636 Cys146Term CCCCCAGCTGTGGGCCTG C GACAACGACCCCGACTGCGAAG TGCg-TGA ATGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTT AAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTTC 3637 GCAGTCGGGGTCGTTGTC G CAGGCCCACAGCTGGGGGATG CAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACAG TGGGCCTG C GACAACGA 3638 TCGTTGTC G CAGGCCCA 3639 Hypercholesterolaemia TGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCATC 3640 Asp147Asn CCCCAGCTGTGGGCCTGC G ACAACGACCCCGACTGCGAAGA cGAC-AAC TGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTT AAAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTT 3641 CGCAGTCGGGGTCGTTGT C GCAGGCCCACAGCTGGGGGAT GCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACA GGGCCTGC G ACAACGAC 3642 GTCGTTGT C GCAGGCCC 3643 Hypercholesterolaemia TGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCATC 3644 Asp147His CCCCAGCTGTGGGCCTGC G ACAACGACCCCGACTGCGAAGA cGAC-CAC TGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTT AAAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTT 3645 CGCAGTCGGGGTCGTTGT C GCAGGCCCACAGCTGGGGGAT GCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACA GGGCCTGC G ACAACGAC 3646 GTCGTTGT C GCAGGCCC 3647 Hypercholesterolaemia TGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCATC 3648 Asp147Tyr CCCCAGCTGTGGGCCTGC G ACAACGACCCCGACTGCGAAGA cGAC-TAC TGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTT AAAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTT 3649 CGCAGTCGGGGTCGTTGT C GCAGGCCCACAGCTGGGGGAT GCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACA GGGCCTGC G ACAACGAC 3650 GTCGTTGT C GCAGGCCC 3651 Hypercholesterolaemia TTCCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGC 3652 Cys152Arg CTGCGACAACGACCCCGAC T GCGAAGATGGCTCGGATGAGT cTGC-CGC GGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGG CCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCGGCCAC 3653 TCATCCGAGCCATCTTCGC A GTCGGGGTCGTTGTCGCAGGC CCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGGAA ACCCCGAC T GCGAAGAT 3654 ATCTTCGC A GTCGGGGT 3655 Hypercholesterolaemia TTCCAGTGCAACAGCTCCACCTGCATGCCCCAGCTGTGGGC 3656 Cys152Gly CTGCGACAACGACCCCGAC T GCGAAGATGGCTCGGATGAGT cTGC-GGC GGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGG CCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCGGCCAC 3657 TCATCCGAGCCATCTTCGC A GTCGGGGTCGTTGTCGCAGGC CCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGGAA ACCCCGAC T GCGAAGAT 3658 ATCTTCGC A GTCGGGGT 3659 Hypercholesterolaemia CCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGCCT 3660 Cys152Trp GCGACAACGACCCCGACTG C GAAGATGGCTCGGATGAGTGG TGCg-TGG CCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGGAC GTCCCCTFGGAACACGTAAAAGACCCCTACAGCGCTGCGGCC 3661 ACTCATCCGAGCCATCTTC G CAGTCGGGGTCGTTGTCGCAG GCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGG CCCGACTG C GAAGATGG 3662 CCATCTTC G CAGTCGGG 3663 Hypercholesterolaemia TGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGCCTGCGA 3664 Asp154Asn CAACGACCCCGACTGCGAA G ATGGCTCGGATGAGTGGCCGC aGAT-AAT AGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGGACAGTA TACTGTCCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCG 3665 GCCACTCATCCGAGCCAT C TTCGCAGTCGGGGTCGTTGTCG CAGGCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGCA ACTGCGAA G ATGGCTCG 3666 CGAGCCAT C TTCGCAGT 3667 Hypercholesterolaemia GCTCCACCTGCATCCCCCAGCTGTGGGCCTGCGACAACGAC 3668 Ser156Leu CCCGACTGCGAAGATGGCT C GGATGAGTGGCCGCAGCGCTG TCG-HG TAGGGGTCTTFACGTGTTCCAAGGGGACAGTAGCCCCTG CAGGGGCTACTGTCCCCTTGGAACACGTAAAGACCCCTACAG 3669 CGCTGCGGCCACTCATCC G AGCCATCTTCGCAGTCGGGGTC GTTGTCGCAGGCCCACAGCTGGGGGATGCAGGTGGAGC AGATGGCT C GGATGAGT 3670 ACTCATCC G AGCCATCT 3671 Hypercholesterolaemia TGTGGGCCTGCGACAACGACCCCGACTGCGAAGATGGCTCG 3672 Cys163Tyr GATGAGTGGCCGCAGCGCT G TAGGGGTCTTTACGTGTTCCAA TGT-TAT GGGGACAGTAGCCCCTGCTCGGCCTTCGAGTTCCACTG CAGTGGAACTCGAAGGCCGAGCAGGGGCTACTGTCCCCTTG 3673 GAACACGTAAAGACCCCTA C AGCGCTGCGGCCACTCATCCG AGCCATCTTCGCAGTCGGGGTCGTTGTCGCAGGCCCACA GCAGCGCT G TAGGGGTC 3674 GACCCCTA C AGCGCTGC 3675 Hypercholesterolaemia CAACGACCCCGACTGCGAAGATGGCTCGGATGAGTGGCCGC 3676 Tyr167Term AGCGCTGTAGGGGTCTTTA C GTGTTCCAAGGGGACAGTAGC TACg-TAG CCCTGCTCGGCCTTCGAGTTCCACTGCCTAAGTGGCGAG CTCGCCACTTAGGCAGTGGAACTCGAAGGCCGAGCAGGGGC 3677 TACTGTCCCCTTGGAACAC G TAAAGACCCCTACAGCGCTGCG GCCACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTTG GGTCTTTA C GTGTTCCA 3678 TGGAACAC G TAAAGACC 3679 Hypercholesterolaemia CCCGACTGCGAAGATGGCTCGGATGAGTGGCCGCAGCGCTG 3680 Gln170Term TAGGGGTCTTTACGTGTTC C AAGGGGACAGTAGCCCCTGCTC cCAA-TAA GGCCHCGAGTTCCACTGCCTAAGTGGCGAGTGCATCC GGATGCACTCGCCACTTAGGCAGTGGAACTCGAAGGCCGAG 3681 CAGGGGCTACTGTCCCCTT G GAACACGTAAAGACCCCTACAG CGCTGCGGCCACTCATCCGAGCCATCTTCGCAGTCGGG ACGTGTTC C AAGGGGAC 3682 GTCCCCTT G GAACACGT 3683 Hypercholesterolaemia CGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTC 3684 Cys176Phe CAAGGGGACAGTAGCCCCT G CTCGGCCTTCGAGTTCCACTG TGC-TTC CCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGA TCACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGCA 3685 GTGGAACTCGAAGGCCGAG C AGGGGCTACTGTCCCCTTGGA ACACGTAAAGACCCCTACAGCGCTGCGGCCACTCATCCG TAGCCCCT G CTCGGCCT 3686 AGGCCGAGCAGGGGCTA 3687 Hypercholesterolaemia CGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTC 3688 Cys176Tyr CAAGGGGACAGTAGCCCCT G CTCGGCCTFCGAGTTCCACTG TGC-TAC CCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGA TCACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGCA 3689 GTGGAACTCGAAGGCCGAG C AGGGGCTACTGTCCCCTTGGA ACACGTAAAGACCCCTACAGCGCTGCGGCCACTCATCCG TAGCCCCT G CTCGGCCT 3690 AGGCCGAG C AGGGGCTA 3691 Hypercholesterolaemia ATGAGTGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAG 3692 Ser177Leu GGGACAGTAGCCCCTGCT C GGCCTTCGAGTTCCACTGCCTA TCG-TTG AGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGATGG CCATCACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAG 3693 GCAGTGGAACTCGAAGGCC G AGCAGGGGCTACTGTCCCCTT GGAACACGTAAAGACCCCTACAGCGCTGCGGCCACTCAT CCCCTGCT C GGCCTTCG 3694 CGAAGGCC G AGCAGGGG 3695 Hypercholesterolaemia TACGTGTTCCAAGGGGACAGTAGCCCCTGCTCGGCCTTCGA 3696 Glu187Lys GTTCCACTGCCTAAGTGGC G AGTGCATCCACTCCAGCTGGC cGAG-AAG GCTGTGATGGTGGCCCCGACTGCAAGGACAAATCTGACG CGTCAGATTTGTCCTTGCAGTCGGGGCCACCATCACAGCGC 3697 CAGCTGGAGTGGATGCACT C GCCACTTAGGCAGTGGAACTC GAAGGCCGAGCAGGGGCTACTGTCCCCTTGGAACACGTA TAAGTGGC G AGTGCATC 3698 GATGCACT C GCCACTTA 3699 Hypercholesterolaemia CAAGGGGACAGTAGCCCCTGCTCGGCCTTCGAGTTCCACTG 3700 His190Tyr CCTPAGTGGCGAGTGCATCCACTC C AGCTGGCGCTGTGATG cCAC-TAC GTGGCCCCGACTGCAAGGACAAATCTGACGAGGAAAACT AGTTTTCCTCGTCAGATTTGTCCTTGCAGTCGGGGCCACCAT 3701 CACAGCGCCAGCTGGAGT G GATGCACTCGCCACTTAGGCAG TGGAACTCGAAGGCCGAGCAGGGGCTACTGTCCCCTTG AGTGCATC C ACTCCAGC 3702 GCTGGAGT G GATGCACT 3703 Hypercholesterolaemia CCTTCGAGTFCCACTGCCTAAGTGGCGAGTGCATCCACTCCA 3704 Gly198Asp GCTGGCGCTGTGATGGTG G CCCCGACTGCAAGGACAAATCT GGC-GAC GACGAGGAAAACTGCGGTATGGGCGGGGCCAGGGTGGG CCCACCCTGGCCCCGCCCATACCGCAGTTTTCCTCGTCAGAT 3705 TTGTCCTTGCAGTCGGGG C CACCATCACAGCGCCAGCTGGA GTGGATGCACTCGCCACTTAGGCAGTGGAACTCGAAGG TGATGGTG G CCCCGACT 3706 AGTCGGGG C CACCATCA 3707 Hypercholesterolaemia GAGTTCCACTGCCTAAGTGGCGAGTGCATCCAGTCCAGCTG 3708 Asp200Asn GCGCTGTGATGGTGGCCCC G ACTGCAAGGACAAATCTGACG cGAC-AAC AGGAAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGG CCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTTCCTCG 3709 TCAGATTTGTCCTTGCAGT C GGGGCCACCATCACAGCGCCAG CTGGAGTGGATGCACTCGCCACTTAGGCAGTGGAACTC GTGGCCCC G ACTGCAAG 3710 CTTGCAGT C GGGGCCAC 3711 Hypercholesterolaemia AGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGC 3712 Asp200Gly GCTGTGATGGTGGCCCCG A CTGCAAGGACAAATCTGACGAG GAC-GGC GAAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGG CCCGCCCCCACCCTGGCCCCGCCCATACCGCAGJTFTCCTC 3713 GTCAGATTTGTCCTTGCAG T CGGGGCCACCATCACAGCGCCA GCTGGAGTGGATGCACTCGCCACTTAGGCAGTGGAACT TGGCCCCG A CTGCAAGG 3714 CCTTGCAG T CGGGGCCA 3715 Hypercholesterolaemia GAGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTG 3716 Asp200Tyr GCGCTGTGATGGTGGCCCC G ACTGCAAGGACAAATCTGACG cGAC-TAC AGGAAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGG CCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTFCCTCG 3717 TCAGATTTGTCCTTGCAG T GGGGGCCACCATCACAGCGCCAG CTGGAGTGGATGCACTCGCCACTTAGGCAGTGGAACTC GTGGCCCC G ACTGCAAG 3718 CTTGCAGT C GGGGCCAC 3719 Hypercholesterolaemia CCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCT 3720 Cys201Term GTGATGGTGGCCCCGACTG C AAGGACAAATCTGACGAGGAA TGCa-TGA AACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGT ACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTT 3721 CCTCGTCAGATTTGTCCTT G CAGTCGGGGCCACCATCACAGC GCCAGCTGGAGTGGATGCACTCGCCACTTAGGCAGTGG CCCGACTG C AAGGACAA 3722 TTGTCCTT G CAGTCGGG 3723 Hypercholesterolaemia TCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGC 3724 Cys201Tyr TGTGATGGTGGCCCCGACT G CAAGGACAAATCTGACGAGGA TGC-TAC AAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCG CGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTTC 3725 CTCGTCAGATTTGTCCTTG C AGTCGGGGCCACCATCACAGCG CCAGCTGGAGTGGATGCACTCGCCACTTAGGCAGTGGA CCCCGACT G CAAGGACA 3726 TGTCCTTG C AGTCGGGG 3727 Hypercholesterolaemia TGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGA 3728 Asp203Asn TGGTGGCCCCGACTGCAAG G ACAAATCTGACGAGGAAAACT gGAC-AAC GCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGTCGTA TAGGACGCCCCCGCCCCCACCCTGGCCCCGCCCATACCGCA 3729 GTTTTCCTCGTCAGATTTGT C CTTGCAGTCGGGGCCACCATC ACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGCA ACTGCAAG G ACAAATCT 3730 AGATTTGT C CTTGCAGT 3731 Hypercholesterolaemia GCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGAT 3732 Asp203Gly GGTGGCCCCGACTGCAAGG A CAAATCTGACGAGGAAAACTG GAC-GGC CGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTAT ATAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCA 3733 GTTTTCCTCGTCAGATTTG T CCTTGCAGTCGGGGCCACCATC ACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGC CTGCAAGG A CAAATCTG 3734 CAGATTTG T CCTTGCAG 3735 Hypercholesterolaemia GCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGAT 3736 Asp203Val GGTGGCCCCGACTGCAAGG A CAAATCTGACGAGGAAAACTG GAC-GTC CGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTAT ATAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCA 3737 GTTTTCCTCGTCAGATTTG T CCTTGCAGTCGGGGCCACCATC ACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGC CTGCAAGG A CAAATCTG 3738 CAGATTTG T CCTTGCAG 3739 Hypercholesterolaemia AGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGG 3740 Ser205Pro CCCCGACTGCAAGGACAAA T CTGACGAGGAAAACTGCGGTAT aTCT-CCT GGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCT AGGTGATAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATA 3741 CCGCAGTTTTCCTCGTCAG A TTTGTCCTTGCAGTCGGGGCCA CCATCACAGCGCCAGCTGGAGTGGATGCACTCGCCACT AGGACAAA T CTGACGAG 3742 CTGGTCAG A TTTGTCCT 3743 Hypercholesterolaemia CGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCG 3744 Asp206Glu ACTGCAAGGACAAATCTGA C GAGGAAAACTGCGGTATGGGC GACg-GAG GGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCC GGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCCG 3745 CCCATACCGCAGTTTTCCTC G TCAGATTTGTCCTTGCAGTCG GGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTCG AAATCTGA C GAGGAAAA 3746 TTTTCCTC G TCAGATTT 3747 Hypercholesterolaemia GAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCGA 3748 Glu207Gln CTGCAAGGACAAATCTGAC G AGGAAAACTGCGGTATGGGCG cGAG-CAG GGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCCT AGGGACAGGTGATAGGACGCCCCGCCCCCACGCTGGCCCC 3749 GCCCATACCGCAGTTTTCCT C GTCAGATTTGTCCTTGCAGTC GGGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTC AATCTGAC G AGGAAAAC 3750 GTTTTCCT C GTCAGATT 3751 Hypercholesterolaemia GAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCGA 3752 Glu207Lys CTGCAAGGACPAATCTGAC G AGGAAAACTGCGGTATGGGCG cGAG-AAG GGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCCT AGGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCC 3753 GCCCATACCGCAGTTTTCCTCGT C AGATTTGTCCTTGCAGTC GGGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTC AATCTGAC G AGGAAAAC 3754 GTTTTCCT C GTCAGATT 3755 Hypercholesterolaemia GAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCGA 3756 Glu207Term CTGCAAGGACAAATCTGAC G AGGAAAACTGCGGTATGGGCG cGAG-TAG GGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCCT AGGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCC 3757 GCCCATACCGCAGTTTTCCT C GTCAGATTTGTCCTTGCAGTC GGGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTC AATCTGAC G AGGAAAAC 3758 GTTTTCCT C GTCAGATT 3759 Hypercholesterolaemia TCTTGAGAAAATCAACACACTCTGTCCTGTTTTCCAGCTGTGG 3760 Glu219Lys CCACCTGTCGCCCTGAC G AATTCCAGTGCTCTGATGGAAACT cGAA-AAA GCATCCATGGCAGCCGGCAGTGTGACCGGGAATATG CATATTCCCGGTCACACTGCCGGCTGCCATGGATGCAGTTTC 3761 CATCAGAGCACTGGAATT C GTCAGGGCGACAGGTGGCCACA GCTGGAAAACAGGACAGAGTGTGTTGATTTTCTCAAGA GCCCTGAC G AATTCCAG 3762 CTGGAATT C GTCAGGGC 3763 Hypercholesterolaemia GAAAATCAACACACTCTGTCCTGTTYFCCAGGTGTGGCCACCT 3764 Gln221Term GTCGCCCTGACGAATTC C AGTGCTCTGATGGAAACTGCATCC cCAG-TAG ATGGCAGCCGGCAGTGTGACCGGGAATATGACTGCA TGCAGTCATATTCCCGGTCACACTGCCGGCTGCCATGGATGC 3765 AGTTTCCATCAGAGCACT G GAATTCGTCAGGGCGACAGGTGG CCACAGCTGGAAAACAGGACAGAGTGTGTTGATTTTC ACGAATTC C AGTGCTCT 3766 AGAGCACT G GAATTCGT 3767 Hypercholesterolaemia CCTGTTTTCCAGCTGTGGCCACCTGTCGCCCTGACGAATTCC 3768 Cys227Phe AGTGCTCTGATGGAAACT G CATCCATGGCAGCCGGCAGTGT TGC-TTC GACCGGGAATATGACTGCAAGGACATGAGCGATGAAGT ACTTCATCGCTCATGTCCTTGCAGTCATATTCCCGGTCACACT 3769 GCCGGCTGCCATGGATG C AGTTTCCATCAGAGCACTGGAATT CGTCAGGGCGACAGGTGGCCACAGCTGGAAAACAGG TGGAAACT G CATCCATG 3770 CATGGATG C AGTTTCCA 3771 Hypercholesterolaemia TCGCCCTGACGAATTCCAGTGCTCTGATGGAAACTGCATCCA 3772 Asp235Glu TGGCAGCCGGCAGTGTGA C CGGGAATATGACTGCAAGGACA GACc-GAA TGAGCGATGAAGTTGGTTAATGGTGAGCGCTGG CCAGCGCTCACCATTAACGCAGCCAACTTCATCGCTCATGTC 3773 CTTGCAGTCATATTCCCG G TCACACTGCCGGCTGCCATGGAT GCAGTTTCCATCAGAGCACTGGAATTCGTCAGGGCGA CAGTGTGA C CGGGAATA 3774 TATTCCCG G TCACACTG 3775 Hypercholesterolaemia GTCGCCCTGACGAATTCCAGTGCTCTGATGGAAACTGCATCC 3776 Asp235Gly ATGGCAGCCGGCAGTGTG A CCGGGAATATGACTGCAAGGAC GAC-GGC ATGAGCGATGAAGTTGGCTGCGTTAATGGTGAGCGCTG CAGCGCTCACCATTAACGCAGCCAACTTCATCGCTCATGTCC 3777 TTGCAGTCATATTCCCGG T CACACTGCCGGCTGCCATGGATG CAGTTTCCATCAGAGCACTGGAATFCGTCAGGGCGAC GCAGTGTG A CCGGGAAT 3778 ATTCCCGG T CACACTGC 3779 Hypercholesterolaemia CCTGACGAATTCCAGTGCTCTGATGGAAACTGCATCCATGGC 3780 Glu237Lys AGCCGGCAGTGTGACCGG G AATATGACTGCAAGGACATGAG gGAA-AAA CGATGAAGTTGGCTGCGTTAATGGTGAGCGCTGGCCAT ATGGCCAGCGCTCACCATTAACGCAGCCAACTTCATCGCTCA 3781 TGTCCTTGCAGTCATATT C CCGGTCACACTGCCGGCTGCCAT GGATGCAGTTTCCATCAGAGCACTGGAATTCGTCAGG GTGACCGG G AATATGAC 3782 GTCATATT C CCGGTCAC 3783 Hypercholesterolaemia TCCAGTGCTCTGATGGAAACTGCATCCATGGCAGCCGGCAGT 3784 Cys240Phe GTGACCGGGAATATGACT G CAAGGACATGAGCGATGAAGTTG TGC-TTC GCTGCGTTAATGGTGAGCGCTGGCCATCTGGTTFTCC GGAAAACCAGATGGCCAGCGCTCACCABAACGCAGCCAACT 3785 TCATCGCTCATGTCCTTG C AGTCATATTCCCGGTCACACTGC CGGCTGCCATGGATGCAGTTTCCATCAGAGCACTGGA ATATGACT G CAAGGACA 3786 TGTCCTTG C AGTCATAT 3787 Hypercholesterolaemia AAACTGCATCCATGGCAGCCGGCAGTGTGACCGGGAATATG 3788 Asp245Glu ACTGCAAGGACATGAGCGA T GAAGTTGGCTGCGTTAATGGTG GATg-GAA AGCGCTGGCCATCTGGTTTTCCATCCCCCATTCTCTGT ACAGAGAATGGGGGATGGAAAACCAGATGGCCAGCGCTCAC 3789 CATTAACGGAGCCAACTTC A TCGCTCATGTCCTTGCAGTCATA TTCCCGGTCACACTGCCGGCTGCCATGGATGCAGTTT ATGAGCGA T GAAGTTGG 3790 CCAACTTC A TCGCTCAT 3791 Hypercholesterolaemia ATGGCAGCCGGCAGTGTGACCGGGAATATGACTGCAAGGAC 3792 Cys249Tyr ATGAGCGATGAAGTTGGCT G CGTTAATGGTGAGCGCTGGCC TGC-TAC ATCTGGTTTTCCATCCCCCATTCTCTGTGCCTTGCTGCT AGCAGCAAGGCACAGAGAATGGGGGATGGAAAACCAGATGG 3793 CCAGCGCTCACCATTAACG C AGCCAACTTCATCGCTCATGTC CTTGCAGTCATATTCCCGGTCACACTGCCGGCTGCCAT AGTTGGCT G CGTTAATG 3794 CATTAACGCAGCCAACT 3795 Hypercholesterolaemia AGGCTCAGACACACCTGACCTTCCTCCTTCCTCTCTCTGGCT 3796 Glu256Lys CTCACAGTGACACTCTGC G AGGGACCCAACAAGTTCAAGTGT cGAG-AAG CACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCA TGCAGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGACACT 3797 TGAACTTGTTGGGTCCCT C GCAGAGTGTCACTGTGAGAGCCA GAGAGAGGAAGGAGGAAGGTCAGGTGTGTCTGAGCCT CACTCTGC G AGGGACCC 3798 GGGTGCCT C GCAGAGTG 3799 Hypercholesterolaemia CCTCTCTCTGGCTCTCACAGTGACACTCTGCGAGGGACCCAA 3800 Ser265Arg CAAGTTCAAGTGTCACAG C GGCGAATGCATCACCCTGGACAA AGCg-AGA AGTCTGCAACATGGCTAGAGACTGCCGGGACTGGTCA TGACCAGTCCCGGCAGTCTCTAGCCATGTTGCAGACTTTGTC 3801 CAGGGTGATGCATTCGCC G CTGTGACACTTGAACTTGTFGGG TCCCTCGCAGAGTGTCACTGTGAGAGCCAGAGAGAGG TGTCACAG C GGCGAATG 3802 CATTCGCC G CTGTGACA 3803 Hypercholesterolaemia TCTCTGGCTCTCACAGTGACACTCTGCGAGGGACCCAACAAG 3804 Glu267Lys TTCAAGTGTCACAGCGGC G AATGCATCACCCTGGACAAAGTC cGAA-AAA TGCAACATGGCTAGAGACTGCCGGGACTGGTCAGATG CATCTGACCAGTCCCGGCAGTCTCTAGCCATGTTGCAGACTT 3805 TGTCCAGGGTGATGCATT C GCCGCTGTGACACTTGAACTTGT TGGGTCCCTCGCAGAGTGTCACTGTGAGAGCCAGAGA ACAGCGGC G AATGCATC 3806 GATGCATT C GCCGCTGT 3807 Hypercholesterolaemia TCTCTGGCTCTGACAGTGACACTCTGCGAGGGACCCAACAAG 3808 Glu267Term TTCAAGTGTCACAGCGGC G AATGCATCACCCTGGACAAAGTC cGAA-TAA TGCAACATGGCTAGAGACTGCCGGGACTGGTCAGATG CATCTGACCAGTCCCGGCAGTCTCTAGCCATGTTGCAGACTT 3809 TGTCCAGGGTGATGCATT C GCCGCTGTGACACTTGAACTFGT TGGGTCCCTCGCAGAGTGTCACTGTGAGAGCCAGAGA ACAGCGGC G AATGCATC 3810 GATGCATT C GCCGCTGT 3811 Hypercholesterolaemia ACACTCTGCGAGGGACCCAACAAGTTCAAGTGTCACAGCGG 3812 Lys273Glu CGAATGCATCACCCTGGAC A AAGTCTGCAACATGGCTAGAGA cAAA-GAA CTGCCGGGACTGGTCAGATGAACCCATCAAAGAGTGCG CGCACTCTTTGATGGGTTCATCTGACCAGTCCCGGCAGTCTC 3813 TAGCCATGTTGCAGACTT T GTCCAGGGTGATGCATTCGCCGC TGTGACACTTGAACTTGTTGGGTCCCTCGCAGAGTGT CCCTGGAC A AAGTCTGC 3814 GCAGACTT T GTCCAGGG 3815 Hypercholesterolaemia CGAGGGACCCAACAAGTTCAAGTGTCACAGCGGCGAATGCA 3816 Cys275Term TCACCCTGGACAAAGTCTG C AACATGGCTAGAGACTGCCGG TGCa-TGA GACTGGTCAGATGAACCCATCAAAGAGTGCGGTGAGTCT AGACTCACCGCACTCTTTGATGGGTTCATCTGACCAGTCCCG 3817 GCAGTCTCTAGCCATGTT G CAGACTTFGTCCAGGGTGATGCA TTCGCCGCTGTGACACTTGAACTTGTTGGGTCCCTCG AAAGTCTG C AACATGGC 3818 GCCATGTT G CAGACTTT 3819 Hypercholesterolaemia AGTTCAAGTGTCACAGCGGCGAATGCATCACCCTGGACAAAG 3820 Asp280Gly TCTGCAACATGGCTAGAG A CTGCCGGGACTGGTCAGATGAA GAC-GGC CCCATCAAAGAGTGCGGTGAGTCTCGGTGCAGGCGGCT AGCCGCCTGCACCGAGACTCACCGCACTCTTTGATGGGTTCA 3821 TCTGACCAGTCCCGGCAG T CTCTAGCCATGTTGCAGACTTTG TCCAGGGTGATGCATTCGCCGCTGTGACACTTGAACT GGCTAGAG A CTGCCGGG 3822 CCCGGCAG T CTCTAGCC 3823 Hypercholesterolaemia TCAAGTGTCACAGCGGCGAATGCATCACCCTGGACAAAGTCT 3824 Cys281Tyr GCAACATGGCTAGAGACT G CCGGGACTGGTCAGATGAACCC TGC-TAC ATCAAAGAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGC GCAAGCCGCCTGCACCGAGACTCACCGCACTCTTTGATGGG 3825 TTCATCTGACCAGTCCCGG C AGTCTCTAGCCATGTTGCAGAC TTTGTCCAGGGTGATGCATTCGCCGCTGTGACACTTGA TAGAGACT G CCGGGACT 3826 AGTCCCGG C AGTCTCTA 3827 Hypercholesterolaemia TGTCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAAC 3828 Asp283Asn ATGGCTAGAGACTGCCGG G ACTGGTCAGATGAACCCATCAAA gGAC-AAC GAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGT ACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACTCTTTGA 3829 TGGGTTCATCTGACCAGT C CCGGCAGTCTCTAGCCATGTTGC AGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGACA ACTGCCGG G ACTGGTCA 3830 TGACCAGT C CCGGCAGT 3831 Hypercholesterolaemia TCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAACAT 3832 Asp283Glu GGCTAGAGACTGCCGGGA C TGGTCAGATGAACCCATCAAAG GACt-GAG AGTGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTTT AAACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACTCTTT 3833 GATGGGTTCATCTGACCA G TCCCGGCAGTCTCTAGCCATGTT GCAGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGA TGCCGGGA C TGGTCAGA 3834 TCTGACCA G TCCCGGCA 3835 Hypercholesterolaemia TGTCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAAC 3836 Asp283Tyr ATGGCTAGAGACTGCCGG G ACTGGTCAGATGAACCCATCAAA gGAC-TAC GAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGT ACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACTCTTTGA 3837 TGGGTTCATCTGACCAGT C CCGGCAGTCTCTAGCCATGTTGC AGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGACA ACTGCCGG G ACTGGTCA 3838 TGACCAGT C CCGGCAGT 3839 Hypercholesterolaemia CAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAACATGG 3840 Trp284Term CTAGAGACTGCCGGGACTG G TCAGATGAACCCATCTAAAGAGT TGGt-TGA GCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTTTGTG CACTAAACTCTGCAAGCCGCCTGCACCGAGACTGACCGCACT 3841 CTTTGATGGGTTCATCTGA C CAGTCCCGGCAGTCTCTAGCCA TGTTGCAGACTTFGTCCAGGGTGATGCATTCGCCGCTG CGGGACTG G TCAGATGA 3842 TCATCTGA C CAGTCCCG 3843 Hypercholesterolaemia GCGGCGAATGCATCACCCTGGACAAAGTCTGCAACATGGCTA 3844 Ser285Leu GAGACTGCCGGGACTGGT C AGATGAACCCATCAAAGAGTGC TCA-TTA GGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTTTGTGGG CCCACAAACTCTGCAAGCCGCCTGCACCGAGACTCACCGCA 3845 CTCTTTGATGGGTTCATCT G ACCAGTCCCGGCAGTCTCTAGC CATGTTGCAGACTTTGTCCAGGGTGATGCATTCGCCGC GGACTGGT C AGATGAAC 3846 GTTCATCT G ACCAGTCC 3847 Hypercholesterolaemia CCCTGGACTAAAGTCTGCAACATGGCTAGAGACTGCCGGGAC 3848 Lys290Arg TGGTCAGATGAACCCATCA A AGAGTGCGGTGAGTCTCGGTG AAA-AGA CAGGCGGCTTGCAGAGTTTGTGGGGAGCCAGGAAAGGGA TCCCTTTCGTGGCTCCCCACAAACTCTGCAAGCCGCCTGCAC 3849 CGAGACTCACCGCACTCT T TGATGGGTTCATCTGACCAGTCC CGGCAGTCTCTAGCCATGTTGCAGACTTTGTCCAGGG ACCCATCA A AGAGTGCG 3850 CGCACTCT T TGATGGGT 3851 Hypercholesterolaemia GGGTAGGGGCCCGAGAGTGACCAGTCTGCATCCCCTGGCCC 3852 Cys297Phe TGCGCAGGGACCAACGAAT G CTTGGACAACAACGGCGGCTG TGC-TTC TTCCCACGTCTGCAATGACCTTAAGATCGGCTACGAGTG CACTCGTAGCCGATCTTAAGGTCATTGCAGACGTGGGAACAG 3853 CCGCCGTTGTTGTCCAAG C ATTCGTTGGTCCCTGCGCAGGG CCAGGGGATGCAGACTGGTCACTCTCGGGCCCCTACCC CAACGAAT G CTTGGACA 3854 TGTCCAAG C ATTCGTTG 3855 Hypercholesterolaemia GGGTAGGGGCCCGAGAGTGACCAGTCTGCATCCCCTGGCCC 3856 Cys297Tyr TGCGCAGGGACCAACGAAT G CTTGGACAACAACGGCGGCTG TGC-TAC TTCCCACGTCTGCAATGACCTTAAGATCGGCTACGAGTG CACTCGTAGCCGATCTTAAGGTCATTGCAGACGTGGGAACAG 3857 CCGCCGTTGTTGTCCAAG C ATTCGTTGGTCCCTGCGCAGGG CCAGGGGATGCAGACTGGTCACTCTCGGGCCCCTACCC CAACGAAT G CTTGGACA 3858 TGTCCAAG C ATTCGTTG 3859 Hypercholesterolaemia TGCATCCCCTGGCCCTGCGCAGGGACCAACGAATGCTTGGA 3860 His306Tyr CAACAACGGCGGCTGTTCC C ACGTCTGCAATGACCTTAAGAT cCAC-TAC CGGCTACGAGTGCCTGTGCCCCGACGGCTTCCAGCTGG CCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTAGCCGATC 3861 TTAAGGTCATTGCAGACGT G GGAACAGCCGCCGTTGTTGTCC AAGCATTCGTTGGTCCCTGCGCAGGGCCAGGGGATGCA GCTGTTCC C ACGTCTGC 3862 GCAGACGT G GGAACAGC 3863 Hypercholesterolaemia CCCTGGCCCTGCGCAGGGACCAACGAATGCTTGGACAACAA 3864 Cys308Gly CGGCGGCTGTTCCCACGTC T GCAATGACCTTAAGATCGGCTA cTGC-GGC CGAGTGCCTGTGCCCCGACGGCTTCCAGCTGGTGGCCC GGGCCACCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTA 3865 GCCGATCTTAAGGTCATTGC A GACGTGGGAACAGCCGCCGT TGTTGTCCAAGCATTCGTTGGTCCCTGCGCAGGGCCAGGG CCCACGTC T GCAATGAC 3866 GTCATTGC A GACGTGGG 3867 Hypercholesterolaemia CCTGGCCCTGCGCAGGGACCAACGAATGCTTGGACAACAAC 3868 Cys308Tyr GGCGGCTGTTCCCACGTCT G CAATGACCTTAAGATCGGCTAC TGC-TAC GAGTGCCTGTGCCCCGACGGCTTCCAGCTGGTGGCCCA TGGGCCACCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTA 3869 GCCGATCTTAAGGTCATTG C AGACGTGGGAACAGCCGCCGTT GTTGTCCAAGCATTCGTTGGTCCCTGCGCAGGGCCAGG CCACGTCT G CAATGACC 3870 GGTCATTG C AGACGTGG 3871 Hypercholesterolaemia ACCAACGAATGCTTGGACAACAACGGCGGCTGTTCGCACGTC 3872 Gly314Ser TGCAATGACCTTAAGATC G GCTACGAGTGGCTGTGCCCCGAC cGGC-AGC GGCTTCCAGCTGGTGGCCCAGCGAAGATGCGAAGGTG CACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAGCCGTCG 3873 GGGCACAGGCACTCGTAGC C GATCTTAAGGTCATTGCAGAC GTGGGAACAGCCGCCGTTGTTGTCCAAGCATTCGTTGGT TTAAGATC G GCTACGAG 3874 CTCGTAGC C GATCTTAA 3875 Hypercholesterolaemia CCAACGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTCT 3876 Gly314Val GCAATGACCTTAAGATCG G CTACGAGTGCCTGTGCCCCGAC GGC-GTC GGCTTCCAGCTGGTGGCCCAGCGAAGATGCGAAGGTGA TCACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAGCCGTC 3877 GGGGCACAGGCACTCGTAG C CGATCTTAAGGTCATTGCAGA CGTGGGAACAGCCGCCGTTGTTGTCCAAGCATTCGTTGG TAAGATCG G CTACGAGT 3878 ACTCGTAG C CGATCTTA 3879 Hyperchoesterolaemia CGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAA 3880 Tyr315Term TGACCTTAAGATCGGCTA C GAGTGCCTGTGCCCCGACGGCTT TACg-TAA CCAGCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTC GAAATCACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAGCC 3881 GTCGGGGCACAGGCACTC G TAGCCGATCTTAAGGTCATTGCA GACGTGGGAACAGCCGCCGTTGTTGTCCAAGCATTCG ATCGGCTACGAGTGCCT 3882 AGGCACTC G TAGCCGAT 3883 Hypercholesterolaemia TGCTTGGACAACTAACGGCGGCTGTTCCCACGTCTGCAATGAC 3884 Cys317Gly CTTAAGATCGGCTACGAG T GCCTGTGCCCCGACGGCTTCCA gTGC-GGC GCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTCCGGG CCCGGAAAATCACCTTCGCATCTTCGCTGGGCCACCAGCTGG 3885 AAGCCGTCGGGGCACAGGC A CTCGTAGCCGATCTTAAGGTC ATTGCAGACGTGGGAACAGCCGCCGTTGTTGTCCAAGCA GCTACGAG T GCCTGTGC 3886 GCACAGGC A CTCGTAGC 3887 Hypercholesterolaemia TGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAATGAC 3888 Cys317Ser CTTAAGATCGGCTACGAG T GCCTGTGCCCCGACGGCTTCCA gTGC-AGC GCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTCCGGG CCCGGAAATCACCTFCGCATCTTCGCTGGGCCACCAGCTGG 3889 AAGCCGTCGGGGCACAGGC A CTCGTAGCCGATCTTAAGGTC ATTGCAGACGTGGGAACAGCCGCCGTTGTTGTCCAAGCA GCTACGAG T GCCTGTGC 3890 GCACAGGC A CTCGTAGC 3891 Hypercholesterlaemia ACAACGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCG 3892 Pro320Arg GCTACGAGTGCCTGTGCC C CGACGGCTTCCAGCTGGTGGCC CCC-CGC CAGCGAAGATGCGAAGGTGATTTCCGGGTGGGACTGAG CTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCTGGGCC 3893 ACCAGCTGGAAGCCGTCG G GGCACAGGCACTCGTAGCCGAT CTTAAGGTCATTGCAGACGTGGGAACAGCCGCCGTTGT CCTGTGCC C CGACGGCT 3894 AGCCGTCG G GGCACAGG 3895 Hypercholesterolaemia AACGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCGGC 3896 Asp321Asn TACGAGTGCCTGTGCCCC G ACGGCTTCCAGCTGGTGGCCCA cGAC-AAC GCGAAGATGCGAAGGTGATTTCCGGGTGGGACTGAGCC GGCTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCTGGG 3897 CCACCAGCTGGAAGCCGT C GGGGCACAGGCACTCGTAGCCG ATCTTAAGGTCATTGCAGACGTGGGAACAGCCGCCGTT TGTGCCCC G ACGGCTTC 3898 GAAGCCGT C GGGGCACA 3899 Hypercholesterolaemia CGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCGGCTA 3900 Asp321Glu CGAGTGCCTGTGCCCCGA C GGCTTCCAGCTGGTGGCCCAGC GACg-GAG GAAGATGCGAAGGTGATTTCCGGGTGGGACTGAGCCCT AGGGCTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCTG 3901 GGCCACCAGCTGGAAGCC G TCGGGGCACAGGCACTCGTAG CCGATCTTAAGGTCATTGCAGACGTGGGAACAGCCGCCG TGCCCCGA C GGCTTCCA 3902 TGGAAGCCGTCGGGGCA 3903 Hypercholesterolaemia GGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCGGCTAC 3904 Gly322Ser GAGTGCCTGTGCCCCGAC G GCTTCCAGCTGGTGGCCCAGCG cGGC-AGC AAGATGCGAAGGTGATTTCCGGGTGGGACTGAGCCCTG CAGGGCTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCT 3905 GGGCCACCAGCTGGAAGC C GTCGGGGCACAGGCACTCGTA GCCGATCTTAAGGTCATTGCAGACGTGGGAACAGCCGGC GCCCCGAC G GCTTCCAG 3906 CTGGAAGC C GTCGGGGC 3907 Hypercholesterolaemia TGTTCCCACGTCTGCAATGACCTTAAGATCGGCTACGAGTGC 3908 Gln324Term CTGTGCCCCGACGGCTTC C AGCTGGTGGCCCAGCGAAGATG cCAG-TAG CGAAGGTGATTTCCGGGTGGGACTGAGCCCTGGGCCCC GGGGCCCAGGGCTCAGTCCCACCCGGAAATCACCTTCGCAT 3909 CTTCGCTGGGCCACCAGCT G GAAGCCGTCGGGGCACAGGCA CTCGTAGCCGATCTTAAGGTCATTGCAGACGTGGGAACA ACGGCTTC C AGCTGGTG 3910 CACCAGCT G GAAGCCGT 3911 Hypercholesterolaemia ATGACCTTAAGATCGGCTACGAGTGCCTGTGCCCCGACGGC 3912 Arg329Pro TTCCAGCTGGTGGCCCAGC G AAGATGCGAAGGTGATTTCCG CGA-CCA GGTGGGACTGAGCCCTGGGCCCGCTCTGCGCTTCCTGAC GTCAGGAAGCGCAGAGGGGGCCCAGGGCTCAGTCCCACCC 3913 GGAAATCACCTTCGCATCTT C GCTGGGCCACCAGCTGGAAG CCGTCGGGGCACAGGCACTCGTAGCCGATCTTAAGGTCAT GGCCCAGC G AAGATGCG 3914 CGCATCTTCGCTGGGCC 3915 Hypercholesterolaemia AATGACCTTAAGATCGGCTACGAGTGCCTGTGCCCCGACGG 3916 Arg329Term CTTCCAGCTGGTGGCCCAG C GAAGATGCGAAGGTGATTTCC gCGA-TGA GGGTGGGACTGAGCCCTGGGCCCCCTCTGCGCTTCCTGA TCAGGAAGCGCAGAGGGGGCCCAGGGCTCAGTCCCACCCG 3917 GAAATCACCTTCGCATCTTC G CTGGGCCACCAGCTGGAAGCC GTCGGGGCACAGGCACTCGTAGCCGATCTTAAGGTCATT TGGCCCAG C GAAGATGC 3918 GCATCTTC G CTGGGCCA 3919 Hypercholesterolaemia TCTAGCCATTGGGGAAGAGCCTCCCCACCAAGCCTCTTTCTC 3920 Glu336Lys TCTCTTCCAGATATCGAT G AGTGTCAGGATCCCGACACCTGC tGAG-AAG AGCCAGCTCTGCGTGAACCTGGAGGGTGGCTACAAGT ACTTGTAGCCACCCTCCAGGTTCACGCAGAGCTGGCTGCAG 3921 GTGTCGGGATCCTGACACT C ATCGATATCTGGAAGAGAGAGA AAGAGGCTTGGTGGGGAGGCTCTTCCCCAATGGCTAGA ATATCGAT G AGTGTCAG 3922 CTGACACT C ATCGATAT 3923 Hypercholesterolaemia CATTGGGGAAGAGCCTCCCCACCAAGCCTCTTTCTCTCTCTT 3924 Gln338Term CCAGATATCGATGAGTGT C AGGATCCCGACACCTGCAGCCAG tCAG-TAG CTCTGCGTGAACCTGGAGGGTGGCTACAAGTGCCAGT ACTGGCACTTGTAGCCACCCTCCAGGTTCACGCAGAGCTGG 3925 CTGCAGGTGTCGGGATCCT G ACACTCATCGATATCTGGAAGA GAGAGAAAGAGGCTTGGTGGGGAGGCTCTTCCCCAATG ATGAGTGT C AGGATCCC 3926 GGGATCCT G ACACTCAT 3927 Hypercholesterolaemia TCCCCACCAAGCCTCTTFCTCTCTCTTCCAGATATCGATGAGT 3928 Cys343Arg GTCAGGATCCCGACACC T GCAGCCAGCTCTGCGTGAACCTG cTGC-CGC GAGGGTGGCTACAAGTGCCAGTGTGAGGAAGGCTTCC GGAAGCCTTCCTCACACTGGCACTTGTAGCCACCCTCCAGGT 3929 TCACGCAGAGCTGGCTGC A GGTGTCGGGATCCTGACACTCA TCGATATCTGGAAGAGAGAGAAAGAGGCTTGGTGGGGA CCGACACC T GCAGCCAG 3930 CTGGCTGC A GGTGTCGG 3931 Hypercholesterolaemia CAAGCCTCTTTCTCTCTCTTCCAGATATCGATGAGTGTCAGGA 3932 Gln345Arg TCCCGACACCTGCAGCC A GCTCTGCGTGAACCTGGAGGGTG CAG-CGG GCTACAAGTGCCAGTGTGAGGAAGGCTTCCAGCTGGA TCCAGCTGGAAGCCTTCCTCAGACTGGCACTTGTAGCCACCC 3933 TCCAGGTTCACGCAGAGC T GGCTGCAGGTGTCGGGATCCTG ACACTCATCGATATCTGGAAGAGAGAGAAAGAGGCTTG CTGCAGCC A GCTCTGCG 3934 CGCAGAGC T GGCTGCAG 3935 Hypercholesterolaemia TCTTTCTCTCTCTTCCAGATATCGATGAGTGTCAGGATCCCGA 3936 Cys347Tyr CACCTGCAGCCAGCTCT G CGTGAACCTGGAGGGTGGCTACA TGC-TAC AGTGCCAGTGTGAGGAAGGCTTCCAGCTGGACCCCCA TGGGGGTCCAGCTGGAAGCCTTCCTCACACTGGCACTTGTA 3937 GCCACCCTCCAGGTTCACG C AGAGCTGGCTGCAGGTGTCGG GATCCTGACAGTCATCGATATCTGGAAGAGAGAGAAAGA CCAGCTCT G CGTGAACC 3938 GGTTCACG C AGAGCTGG 3939 Hypercholesterolaemia CTCTTTCTCTCTCTTCCAGATATCGATGAGTGTCAGGATCCCG 3940 Cys347Arg ACACCTGCAGCCAGCTC T GCGTGAACCTGGAGGGTGGCTAC cTGC-CGC AAGTGCCAGTGTGAGGAAGGCTTCCAGCTGGACCCCC GGGGGTCCAGCTGGAAGCCTTCCTCACACTGGCACTTGTAG 3941 CCACCCTCCAGGTTCACGC A GAGCTGGCTGCAGGTGTCGGG ATCCTGACACTCATCGATATCTGGXAGAGAGAGAAAGAG GCCAGCTC T GCGTGAAC 3942 GTTCACGC A GAGCTGGC 3943 Hypercholesterolaemia CAGATATCGATGAGTGTCAGGATCCCGACACCTGCAGCCAGC 3944 Gly352Asp TCTGCGTGAACCTGGAGG G TGGCTACAAGTGCCAGTGTGAG GGT-GAT GAAGGCTTCCAGCTGGACCCCCACACGAAGGCCTGCAA TTGCAGGCCTTCGTGTGGGGGTCCAGCTGGAAGCCTTCCTC 3945 ACACTGGCACTTGTAGCCA C CCTCCAGGTTCACGCAGAGCTG GCTGCAGGTGTCGGGATCCTGACACTCATCGATATCTG CCTGGAGG G TGGCTACA 3946 TGTAGCCA C CCTCCAGG 3947 Hypercholesterolaemia TCGATGAGTGTCAGGATCCCGACACCTGCAGCCAGCTCTGC 3948 Tyr354Cys GTGAACCTGGAGGGTGGCT A CAAGTGCCAGTGTGAGGAAGG TAC-TGC CTTCCAGCTGGACCCCCACACGAAGGCCTGCAAGGCTGT ACAGCCTTGCAGGCCTTCGTGTGGGGGTCCAGCTGGAAGCC 3949 TTCCTCACACTGGCACTTG T AGCCACCCTCCAGGTTCACGCA GAGCTGGCTGCAGGTGTCGGGATCCTGACACTCATCGA GGGTGGCT A CAAGTGCC 3950 GGCACTTG T AGCCACCC 3951 Hypercholesterolaemia CAGGATCCCGACACCTGCAGCCAGGTCTGCGTGAACCTGGA 3952 Cys358Arg GGGTGGCTACAAGTGCCAG T GTGAGGAAGGCTTCCAGCTGG gTGT-CGT ACCCCCACACGAAGGCCTGCAAGGCTGTGGGTGAGCACG CGTGCTCACCCACAGCCTTGCAGGCCTTCGTGTGGGGGTCC 3953 AGCTGGAAGCCTTCCTCAC A CTGGCACTTGTAGCCACCCTCC AGGTTCACGCAGAGCTGGCTGCAGGTGTCGGGATCCTG AGTGCCAG T GTGAGGAA 3954 TTCCTCAC A CTGGCACT 3955 Hypercholesterolaemia TGCAGCCAGCTCTGCGTGAACCTGGAGGGTGGCTACAAGTG 3956 Gln363Term CCAGTGTGAGGAAGGCTTC C AGCTGGACCCCCACACGAAGG cCAG-TAG CCTGCAAGGCTGTGGGTGAGCACGGGAAGGCGGCGGGTG CACCCGCCGCCTTCCCGTGCTCACCCACAGCCTTGCAGGCC 3957 TTCGTGTGGCGGTCCAGCT G GAAGCCTTCCTCACACTGGCA CTTGTAGCCACCCTCCAGGTTCACGCAGAGCTGGCTGCA AAGGCTTC C AGCTGGAC 3958 GTCCAGCTGGAAGCCTT 3959

EXAMPLE 22 UDP-glucuronosyltransferase—UGT1

Mutations in the human UGT1 gene result in a range of disease syndromes, ranging from relatively common diseases such as Gilbert's syndrome, which effects up to 7% of the population, to rare disorders such as Crigler-Najjar syndrome. Symptoms of these diseases are the result of diminished bilirubin conjugation and typically present with jaundice or, when mild, as an incidental finding during routing laboratory analysis. Severe cases of Crigler-Najar syndrome are caused by an absence of UGT1 activity and the majority of these patents die in the neonatal period. The only known treatment is liver transplant. The attached table discloses the correcting oligonucleotide base sequences for the UGT1 oligonucleotides of the invention.

TABLE 29 UGT1 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Crigler-Najjar GCAGGAGCAAAGGCGCCATGGCTGTGGAGTCCCAGGGCGG 3960 syndrome 2 ACGCCCACTTGTCCTGGGCC T GCTGCTGTGTGTGCTGGGCC Leu15Arg CAGTGGTGTCCCATGCTGGGAAGATACTGTTGATCCCAGT CTG-CGG ACTGGGATCAACAGTATCTTCCCAGCATGGGACACCACTGGGCGTCC 3961 CCCAGCACACACAGCAGC A GGCCCAGGACAAGTGGGCGTCC GCCCTGGGACTCCACAGCCATGGCGCCTTTGCTCCTGC CCTGGGCC T GCTGCTGT 3962 ACAGCAGC A GGCCCAGG 33963 Crigler-Najjar GGGAAGATACTGTTGATCCCAGTGGATGGCAGCCACTGGCT 3964 syndrome 1 GAGCATGCTTGGGGCCATC C AGCAGCTGCAGCAGAGGGGAC Gln49Term ATGAAATAGTTGTCCTAGCACCTGACGCCTCGTTGTACA CAG-TAG TGTACAACGAGGCGTCAGGTGCTAGGACAACTATTTCATGTC 3965 CCCTCTGCTGCAGCTGCT G GATGGCCCCAAGCATGCTCAGC CAGTGGCTGCCATCCACTGGGATCAACAGTATGTTCCC GGGCCATC C AGCAGCTG 3966 CAGCTGCT G GATGGCCC 3967 Crigler-Najjar CAGCAGAGGGGACATGAAATAGTTGTCCTAGCACCTGACGCC 3968 syndrome 1 TCGTTGTACATCAGAGAC G GAGCATTTTACACCTTGAAGACGT Gly71Arg ACCCTGTGCCATTCCAAAGGGAGGATGTGAAAGAGT GGA-AGA ACTCTTTCACATCCTCCCTTTGGAATGGCACAGGGTACGTCTT 3969 CAAGGTGTAAAATGCTC C GTCTCTGATGTACAACGAGGCGTC AGGTGCTAGGACAACTATTTCATGTCCCCTCTGCTG TCAGAGAC G GAGCATTT 3970 AAATGCTC C GTCTCTGA 3971 Gilbert syndrome GGGTGAAGAACATGCTCATTGCCVTTTCACAGAACTTTCTGTG 3972 Pro229Gln CGACGTGGTTTATTCCC C GTATGCAACCCTTGCCTCAGAATT CCG-CAG CCTTCAGAGAGAGGTGACTGTCCAGGACCTATTGAG CTCAATAGGTCCTGGACAGTCACCTCTCTCTGAAGGAATTCT 3973 GAGGCAAGGGTTGCATAC G GGGAATAAACCACGTCGCACAG AAGTTCTGTGAAAAGGCAATGAGCATGTTCTTCACCC TTATTCCC C GTATGCAA 3974 TTGCATAC G GGGAATAA 3975 Crigler-Najjar TGTGAAGGATTACCCTAGGCCCATCATGCCCAATATGGTTTTT 3976 syndrome 1 GTTGGTGGTAATCAACTG C CTTCACCAAAATCCACTATCCCAG Cys280Term GTGTGTATTGGAGTGGGACTTTTACATGCGTATATT TGC-TGA AATATACGCATGTAAAAGTCCCACTCCAATACACACCTGGGAT 3977 AGTGGATTTTGGTGAAG G CAGTTGATTCCACCAACAAAAAC ATATTGGGCATGATGGGCCTAGGGTAATCCTTCACA ATCAAACTG C CTTCACCA 3978 TGGTGAAG G CAGTTGAT 3979 Crigler-Najjar ATCAAAGAATATGAGAAAAAATTAACTGAAAATTTTTCTTCTGG 3980 syndrome 1 CTCTAGGAATTTGAAG C CTACATTAATGCTTCTGGAGAACATG Ala292Val GAATTGTGGTTTTCTCTTTGGGATCAATGGTCTC GCC-GTC GAGACCATTGATCCCAAAGAGAAAACCACAATTCCATGTTCTC 3981 CAGAAGCATTAATGTAG G CTTCAAATTCCTAGAGCCAGAAGAA AAATTTTCAGTTAATTTTTTCTCATATTCTTTGAT ATTTGAAG C CTACATTA 3982 taatgtag G CTTCAAAT 3983 Crigler-Najjar AGGAATTTGAAGCCTACATTAATGCTTCTGGAGAACATGGAAT 3984 syndrome 1 TGTGGTTTTCTCTTTGG G ATCAATGGTCTCAGAAATTCCAGAG Gly308Glu AAGAAAGCTATGGCAATTGCTGATGCTTTGGGCAA GGA-GAA TTGCCCAAAGCATCAGCAATTGCCATAGCTTTCTTCTCTGGAA 3985 TTTCTGAGACCATTGAT C CCAAAGAGAAAACCACAATTCCATG TTCTCCAGAAGCATTAATGTAGGCTTCAAATTCCT CTCTTTGG G ATCAATGG 3986 CCATTGAT C CCAAAGAG 3987 Crigler-Najjar GTCTCAGAAATTCCAGAGAAGAAAGCTATGGCAATTGCTGAT 3988 syndrome 1 GCTTTGGGCAAAATCCCT C AGACAGTAAGAAGATTCTATACCA Gln331Term TGGCCTCATATCTATTTTCACAGGAGCGCTAATCCC CAG-TAG GGGATTAGCGCTCCTGTGAAAATAGATATGAGGCCATGGTAT 3989 AGAATCTTCTTACTGTCT G AGGGATTTTGCCCAAAGCATCAGC AATTGCCATAGCTTTCTTCTCTGGAATTTCTGAGAC AAATCCCT C AGACAGTA 3990 TACTGTCT G AGGGATTT 3991 Crigler-Najjar TCTAATCATATTATGTTCTTTCTTTACGTTCTGCTCTTTTTGCC 3992 syndrome 1 CCTCCCAGGTCCTGTG G CGGTACACTGGAACCCGACCATCG Trp335Term AATCTTGCGAACAACACGATACTTGTTAAGTGGCTA TGG-TGA TAGCCACTTAACAAGTATCGTGTTGTTCGCAAGATTCGATGGT 3993 CGGGTTCCAGTGTACCG C CACAGGACCTGGGAGGGGCAAAA AGAGCAGAACGTAAAGAAAGAACATAATATGATTAGA GTCCTGTG G CGGTACAC 3994 GTGTACCG C CACAGGAC 3995 Crigler-Najjar ACACTGGAACCCGACCATCGAATCTTGCGAACAACACGATAC 3996 syndrome 1 TTGTTAAGTGGCTACCCC A AAACGATCTGCTTGGTATGTTGG Gln357Arg GCGGATTGGATGTATAGGTCAAACCAGGGTCAAATTA CAA-CGA TAATTTGACCCTGGTTTGACCTATACATCCAATCCGCCCAACA 3997 TACCAAGCAGATCGTTT T GGGGTAGCCACTTAACAAGTATCGT GTTGTTCGCAAGATTCGATGGTCGGGTTCCAGTGT GCTACCCC A AAACGATC 3998 GATCGTTT T GGGGTAGC 3999 Crigler-Najjar TACACTGGAACCCGACCATCGAATCTTGCGAACAACACGATA 4000 syndrome 1 CTTGTTAAGTGGCTACCC C AAAACGATCTGCTTGGTATGTTG Gln357Term GGCGGATTGGATGTATAGGTCAAACCAGGGTCAAATT CAA-TAA AATTTGACCCTGGTTTGACCTATACATCCAATCCGCCCAACAT 4001 ACCAAGCAGATCGTTTT G GGGTAGCCACTTAACAAGTATCGT GTTGTTCGCAAGATTCGATGGTCGGGTTCCAGTGTA GGCTACCC C AAAACGAT 4002 ATCGTTTT G GGGTAGCC 4003 Gilbert syndrome AACTCAGAGATGTAACTGCTGACATCCTCCCTATTTTGCATCT 4004 Arg367Gly CAGGTCACCCGATGACC C GTGCCTTTATCACCCATGCTGGTT CGT-GGT CCCATGGTGTTTATGAAAGCATATGCAATGGCGTTC GAACGCCATTGCATATGCTTTCATAAACACCATGGGAACCAG 4005 CATGGGTGATAAAGGCAC G GGTCATCGGGTGACCTGAGATG CAAAATAGGGAGGATGTCAGCAGTTACATCTCTGAGTT CGATGACC C GTGCCTTT 4006 AAAGGCAC G GGTCATCG 4007 Crigler-Najjar TCAGAGATGTAACTGCTGACATCCTCCCTATTTTGCATCTCAG 4008 syndrome 1 GTCACCCGATGACCCGT G CCTTTATCACCCATGCTGGTTCCC Ala368Thr ATGGTGTTTATGAAAGCATATGCAATGGCGTTCCCA GCC-ACC TGGGAACGCCATTGCATATGCTTTCATAAACACCATGGGAAC 4009 CAGCATGGGTGATAAAGG C ACGGGTCATCGGGTGACCTGAG ATGCAAAATAGGGAGGATGTCAGCAGTTACATCTCTGA TGACCCGT G CCTTTATC 4010 GATAAAGG C ACGGGTCA 4011 Crigler-Najjar CCTCCCTATTTTTGCATCTCAGGTCACCCGATGACCCGTGCCT 4012 syndrome 1 TTATCACCCATGCTGGTT C CCATGGTGTTTATGAAAGCATATG Ser375Phe CAATGGCGTTCCCATGGTGATGATGCCCTTGTTTGG TCC-TTC CCAAACAAGGGCATCATCACCATGGGAACGCCATTGCATATG 4013 CTTTCATAAACACCATGG G AACCAGCATGGGTGATAAAGGCA CGGGTCATCGGGTGACCTGAGATGCAAAATAGGGAGG TGCTGGTT C CCATGGTG 4014 CACCATGG G AACCAGCA 4015 Crigler-Najjar AGGTCACCCGATGACCCGTGCCTTTATCACCCATGCTGGTTC 4016 syndrome 1 CCATGGTGTTTATGAAAG C ATATGCAATGGCGTTCCCATGGT Ser381Arg GATGATGCCCTTGTTTGGTGATCAGATGGACAATGCA AGC-AGG TGCATTGTCCATCTGATCACCAAACAAGGGCATCATCACCAT 4017 GGGAACGCCATTGCATAT G CTTTCATAAACACCATGGGAACC AGCATGGGTGATAAAGGCACGGGTCATCGGGTGACCT TATGAAAG C ATATGCAA 4018 TTGCATAT G CTTTCATA 4019 Crigler-Najjar AGCATATGCAATGGCGTTCCCATGGTGATGATGCCCTTGTTT 4020 syndrome 1 GGTGATCAGATGGACAAT G CAAAGCGCATGGAGACTAAGGG Ala401Pro AGCTGGAGTGACCCTGAATGTTCTGGAAATGACTTCTG GCA-CCA CAGAAGTCATTTCCAGAACATTCAGGGTCACTCCAGCTCCCT 4021 TAGTCTCCATGCGCTTTG C ATTGTCCATCTGATCACCAAACAA GGGCATCATCACCATGGGAACGCCATTGCATATGCT TGGACAAT G CAAAGCGC 4022 GCGCTTTG C ATTGTCCA 4023 Crigler-Najjar GGAGCTGGAGTGACCCTGAATGTTCTGGAAATGACTTCTGAA 4024 syndrome 1 GATTTAGAAAATGCTCTA A AAGCAGTCATCAATGACAAAAGGT Lys428Glu AAGAAAGAAGATACAGAAGAATACTTTGGTCATGGC AAA-GAA GCCATGACCAAAGTATTCTTCTGTATCTTCTTCTTTACCTTTTG 4025 TCATTGATGACTGCTT T TAGAGCATTTTCTAAATGTTCAGAAGT CATTTCCAGAACATTCAGGGTCACTCCAGCTCC ATGCTCTA A AAGCAGTC 4026 GACTGCTT T TAGAGCAT 4027 Crigler-Najjar ATGAGGCACAAGGGCGCGCCACACCTGCGCCCCGCAGCCC 4028 syndrome 1 ACGACCTCACCTGGTACCAG T ACCATTCCTTGGACGTGATTG Tyr486Asp GTTTCCTCTTGGCCGTCGTGCTGACAGTGGCCTTCATCA TAC-GAC TGATGAAGGCCACTGTCAGCACGACGGCCAAGAGGAAACCA 4029 ATCACGTCCAAGGAATGGT A CTGGTACCAGGTGAGGTCGTG GGCTGCGGGGCGCAGGTGTGGCGCGCCCTTGTGCCTCAT GGTACCAG T ACCATTCC 4030 GGAATGGT A CTGGTACC 4031 Crigler-Najjar ACAAGGGCGCGCCACACCTGCGCCCCGCAGCCCACGACCT 4032 syndrome 1 CACCTGGTACCAGTACCATT C CTTGGACGTGATTGGTTTCCT Ser488Phe CTTGGCCGTCGTGCTGACAGTGGCCTTCATCACCTTTAA TCC-UC TTAAAGGTGATGAAGGCCACTGTCAGCACGACGGCCAAGAG 4033 GAAACCAATCACGTCCAAG G AATGGTACTGGTACCAGGTGAG GTCGTGGGCTGCGGGGCGCAGGTGTGGCGCGCCCTTGT GTACCATT C CTTGGACG 4034 CGTCCAAG G AATGGTAC 4035

EXAMPLE 23 Alzheimer's Disease—Amyloid Precursor Protein (APP)

Over the past few decades Alzheimer's disease (AD), once considered a rare disorder, has become recognized as a major public health problem. Although there is no agreement on the exact prevalence of Alzheimer's disease, in part due to difficulties of diagnosis, studies consistently point to an exponential rise in prevalence of this disease with age. After age 65, the percentage of affected people approximately doubles with every decade of life, regardless of definition. Among people age 85 or older, studies suggest that 25 to 35 percent have dementia, including Alzheimer's disease; one study reports that 47.2 percent of people over age 85 have Alzheimer's disease, exclusive of other dementias.

Alzheimer's disease progressively destroys memory, reason, judgment, language, and, eventually, the ability to carry out even the simplest tasks. Anatomic changes associated with Alzheimer's disease begin in the entorhinal cortex, proceed to the hippocampus, and then gradually spread to other regions, particularly the cerebral cortex. Chief among such anatomic changes are the presence of characteristic extracellular plaques and internal neurofibrillary tangles.

At least four genes have been identified to date that contribute to development of Alzheimer's disease: AD1 is caused by mutations in the amyloid precursor gene (APP); AD2 is associated with a particular allele of APOE (see Example 20); AD3 is caused by mutation in a gene encoding a 7-transmembrane domain protein, presenilin-1 (PSEN1), and AD4 is caused by mutation in a gene that encodes a similar 7-transmembrane domain protein, presenilin-2 (PSEN2). The attached table discloses

TABLE 30 APP Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Alzheimer disease CTGCATACTTTAATTATGATGTAATACAGGTTCTGGGTTGACA 4036 Glu665Asp AATATCAAGACGGAGGA G ATCTCTGAAGTGAAGATGGATGCA GAG-GAC GAATTCCGACATGACTCAGGATATGAAGTTCATCAT ATGATGAACTTCATATCCTGAGTCATGTCGGAATTCTGCATCC 4037 ATCTTCACTTCAGAGAT C TCCTCCGTCTTGATATTTGTCAACC CAGAACCTGTATTACATCATAATTAAAGTATGCAG ACGGAGGA G ATCTCTGA 4038 TCAGAGAT C TCCTCCGT 4039 Alzheimer disease ATTATATTGCATTTAGAAATTAAAATTCTTTTTCTTAATTTGTTTT 4040 Ala692Gly CAAGGTGTTCTTTG C AGAAGATGTGGGTTCAAACAAAGGTGC GCA-GGA AATCATTGGACTCATGGTGGGCGGTGTTGTCAT ATGACAACACCGCCCACCATGAGTCCAATGATTGCACCTTTG 4041 TTTGAACCCACATCTTCT G CAAAGAACACCTTGAAAACAAATT AAGAAAAAGAATTTTAATTTCTAAATGCAATATAAT GTTCTTTG C AGAAGATG 4042 CATCTTCT G CAAAGAAC 4043 Alzheimer disease TATATTGCATTTAGAAATTAAAATTCTTTTTCTTAATTTGTTTTC 4044 Glu693Gln AAGGTGTTCTTTGCA G AAGATGTGGGTTCAAACAAAGGTGCA GAA-CAA ATCATTGGACTCATGGTGGGCGGTGTTGTCATAG CTATGACAACACCGCCCACCATGAGTCCAATGATTGCACCTT 4045 TGTTTGAACCCACATCTT C TGCAAAGAACACCTTGAAAACAAA TTAAGAAAAAGAATTTTAATTTCTAAATGCAATATA TCTTTGCAG A AGATGTG 4046 CACATCTTC T GCAAAGA 4047 Alzheimer disease ATATTGCATTTAGAAATTAAAATTCTTTTTCTTAATTTGTTTTCA 4048 Glu693Gly AGGTGTTCTTTGCAG A AGATGTGGGTTCAAACAAAGGTGCAA GAA-GGA TCATTGGACTCATGGTGGGCGGTGTTGTCATAGC GCTATGACAACACCGCCCACCATGAGTCCAATGATTGCACCT 4049 TTGTTTGAACCCACATCT T CTGCAAAGAACACCTTGAAAACAA ATTAAGAAPAAGAATTTTAATTTCTAAATGCAATAT CTTTGCAG A AGATGTGG 4050 CCACATCT T CTGCAAAG 4051 Alzheimer disease GAAGATGTGGGTTCAAACAAAGGTGCAATCATTGGACTCATG 4052 Ala713Thr GTGGGCGGTGTTGTCATA G CGACAGTGATCGTCATCACCTTG GCG-ACG GTGATGCTGAAGAAGAAACAGTACACATCCATTCATC GATGAATGGATGTGTACTGTTTCTTCTTCAGCATCACCAAGGT 4053 GATGACGATCACTGTCG C TATGACAACACCGCCCACCATGAG TCCAATGATTGCACCTTTGTTTGAACCCACATCTT TTGTCATA G CGACAGTG 4054 CACTGTCG C TATGACAA 4055 Schizophrenia AAGATGTGGGTTCAAACAAAGGTGCAATCATTGGACTCATGG 4056 Ala713Val TGGGCGGTGTTGTCATAG C GACAGTGATCGTCATCACCTTGG GCG-GTG TGATGCTGAAGAAGAAACAGTACACATCCATTCATCA TGATGAATGGATGTGTACTGTTTCTTCTTCAGCATCACCAAGG 4057 TGATGACGATCACTGTC G CTATGACAACACCGCCCACCATGA GTCCAATGATTGCACCTTTGTTTGAACCCACATCTT TGTCATAG C GACAGTGA 4058 TCACTGTC G CTATGACA 4059 Alzheimer disease GTGGGTTCAAACAAAGGTGCAATCATTGGACTCATGGTGGGC 4060 Val715Met GGTGTTGTCATAGCGACA G TGATCGTCATCACCTTGGTGATG GTG-ATG CTGAAGAAGAAACAGTACACATCCATTCATCATGGTG CACCATGATGAATGGATGTGTACTGTTTCTTCTTCAGCATCAC 4061 CAAGGTGATGACGATCA C TGTCGCTATGACAACACCGCCCAC CATGAGTCCAATGATTGCACCTTTGTTTGAACCCAC TAGCGACA G TGATCGTC 4062 GACGATCA C TGTCGCTA 4063 Alzheimer disease GGTTCAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGT 4064 Ile716Val GTTGTCATAGCGACAGTG A TCGTCATCACCTTGGTGATGCTG ATC-GTC AAGAAGAAACAGTACACATCCATTCATCATGGTGTGG CCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCAGCAT 4065 CACCAAGGTGATGACGA T CACTGTCGCTATGACAACACCGCC CACCATGAGTCCAATGATTGCACCTTTGTTTGAACC CGACAGTG A TCGTCATC 4066 GATGACGA T CACTGTCG 4067 Alzheimer disease CAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGTGTTG 4068 Val717Gly TCATAGCGACAGTGATCG T CATCACCTTGGTGATGCTGAAGA GTC-GGC AGAAACAGTACACATCCATTCATCATGGTGTGGTGGA TCCACCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCA 4069 GCATCACCAAGGTGATG A CGATCACTGTCGCTATGACAACAC CGCCCACCATGAGTCCAATGATTGCACCTTTGTTTG AGTGATCG T CATCACCT 4070 AGGTGATG A CGATCACT 4071 Aizheimer disease TCAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGTGTT 4072 Val17Ile GTCATAGCGACAGTGATC G TCATCACCTTGGTGATGCTGAAG GTC-ATC AAGAAACAGTACACATCCATTCATCATGGTGTGGTGG CCACCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCAG 4073 CATCACCAAGGTGATGA C GATCACTGTCGCTATGACAACACC GCCCACCATGAGTCCAATGATTGCACCTTTGTTTGA CAGTGATC G TCATCACC 4074 GGTGATGA C GATCACTG 4075 Alzheimer disease TCAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGTGTT 4076 Val717Phe GTCATAGCGACAGTGATC G TCATCACCTTGGTGATGCTGAAG GTC-TTC AAGAAACAGTACACATCCATTCATCATGGTGTGGTGG CCACCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCAG 4077 CATCACCAAGGTGATGA C GATCACTGTCGCTATGACAACACC GCCCACCATGAGTCCAATGATTGCACCTTTGTTTGA CAGTGATC G TCATCACC 4078 GGTGATGA C GATCACTG 4079 Alzheimer disease TTGGACTCATGGTGGGCGGTGTTGTCATAGCGACAGTGATCG 4080 Leu723Pro TCATCACCTTGGTGATGC T GAAGAAGAAACAGTACACATCCAT CTG-CCG TCATCATGGTGTGGTGGAGGTAGGTAAACTTGACTG CAGTCAAGTTTACCTACCTCCACCACACCATGATGAATGGAT 4081 GTGTACTGTTTCTTCTTC A GCATCACCAAGGTGATGACGATCA CTGTCGCTATGACAACACCGCCCACCATGAGTCCAA GGTGATGC T GAAGAAGA 4082 TCTTCTTC A CCATCACC 4083

EXAMPLE 24 Alzheimer's Disease—Presenilin-1 (PSEN1)

The attached table discloses the correcting oligonucleotide base sequences for the PSEN1 oligonucleotides of the invention.

TABLE 31 PSEN1 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Alzheimer disease CCCGGCAGGTGGTGGAGCAAGATGAGGAAGAAGATGAGGAG 4084 Ala79Val CTGACATTGAAATATGGCG C CAAGCATGTGATCATGCTCTTTG GCC-GTC TCCCTGTGACTCTCTGCATGGTGGTGGTCGTGGCTAC GTAGCCACGACCACCACCATGCAGAGAGTCACAGGGACAAA 4085 GAGCATGATCACATGCTTG G CGCCATATTTCAATGTCAGCTC CTCATCTTCTTCCTCATCTTGCTCCACCACCTGCCGGG ATATGGCG C CAAGCATG 4086 CATGCTTG G CGCCATAT 4087 Alzheimer disease GTGGTGGAGCAAGATGAGGAAGAAGATGAGGAGCTGACATT 4088 Val82Leu GAAATATGGCGCCAAGCAT G TGATCATGCTCTTTGTCCCTGT tGTG-CTG GACTCTCTGCATGGTGGTGGTCGTGGCTACCATTAAGT ACTTAAGGTAGCCACGACCACCACCATGCAGAGAGTCACAG 4089 GGACAAAGAGCATGATCA C ATGCTTGGCGCCATATTTCAATG TCAGCTCCTCATCTTCTTCCTCATCTTGCTCCACCAC CCAAGCAT G TGATCATG 4090 CATGATCA C ATGCTTGG 4091 Alzheimer disease AAATATGGCGCCAAGCATGTGATCATGCTCTTTGTCCCTGTG 4092 Val96Phe ACTCTCTGCATGGTGGTG G TCGTGGCTACCATTAAGTCAGTC gGTC-TTC AGCTTTTATACCCGGAAGGATGGGCAGCTGTACGTAT ATACGTACAGCTGCCCATCCTTCCGGGTATAAAAGCTGACTG 4093 ACTTAATGGTAGCCACGA C CACCACCATGCAGAGAGTCACAG GGACAAAGAGCATGATCACATGCTTGGCGCCATATTT TGGTGGTG G TCGTGGCT 4094 AGCCACGA C CACCACCA 4095 Alzheimer disease CTTTGTCCCTGTGACTCTCTGCATGGTGGTGGTCGTGGCTAC 4096 Phe105Leu CATTAAGTCAGTCAGCTT T TATACCCGGAAGGATGGGCAGCT TTTt-TTG GTACGTATGAGTTTTGTTTTATTATTCTCAAAGCCAG CTGGCTTTGAGAATAATAAAACAAAACTCATACGTACAGCTGC 4097 CCATCCTTCCGGGTATA A AAGCTGACTGACTTAATGGTAGCC ACGACCACCACCATGCAGAGAGTCACAGGGACAAAG GTCAGCTT T TATACCCG 4098 CGCGTATA A AAGCTGAC 4099 Alzheimer disease TGGTGATCTCCATTAACACTGACCTAGGGCTTTTGTGTTTGTT 4100 Thr116Asn TTATTGTAGAATCTATA C CCCATTCACAGAAGATACCGAGACT ACC-AAC GTGGGCCAGAGAGCCCTGCACTCAATTCTGAATGC GCATTCAGAATTGAGTGCAGGGCTCTCTGGCCCACAGTCTCG 4101 GTATCTTCTGTGAATGGG G TATAGATTCTACAATAAAACAAAC ACAAAAGCCCTAGGTCAGTGTTAATGGAGATCACCA AATCTATA C CCCATTCA 4102 TGAATGGG G TATAGATT 4103 Alzheimer disease TGATCTCCATTAACACTGACCTAGGGCTTTTGTGTTTGTTTTAT 4104 Pro117Leu TGTAGAATCTATACCC C ATTCACAGAAGATACCGAGACTGTG CCA-CTA GGCCAGAGAGCCCTGCACTCAATTCTGAATGCTGC GCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGCCCACAGTC 4105 TCGGTATCTTCTGTGAAT G GGGTATAGATTCTACAATAAAACA AACACAAAAGCCCTAGGTCAGTGTTAATGGAGATCA CTATACCC C ATTCACAG 4106 CTGTGAAT G GGGTATAG 4107 Alzheimer disease TAACACTGACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAATCT 4108 Glu120Asp ATACCCCATTCACAGA A GATACCGAGACTGTGGGCCAGAGAG GAAg-GAT CCCTGCACTCAATTCTGAATGCTGCCATCATGATC GATCATGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTG 4109 GCCCACAGTCTCGGTATC T TCTGTGAATGGGGTATAGATTCT ACAATAAAACAAACACAAAAGCCCTAGGTCAGTGTTA TTCACAGA A GATACCGA 4110 TCGGTATC T TCTGTGAA 4111 Alzheimer disease TAACACTGACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAATCT 4112 Glu120Asp ATACCCCATTCACAGA A GATACCGAGACTGTGGGCCAGAGAG GAAg-GAC CCCTGCACTCAATTCTGAATGCTGCCATCATGATC GATCATGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTG 4113 GCCCACAGTCTCGGTATC T TCTGTGAATGGGGTATAGATTCT ACAATAAAACAAACACAAAAGCCCTAGGTCAGTGTTA TTCACAGA A GATACCGA 4114 TCGGTATC T TCTGTGAA 4115 Alzheimer disease ATTAACACTGACCTAGGGCTTTTGTGTTTGTTTATTGTAGAAT 4116 Glu120Lys CTATACCCCATTCACA G AAGATACCGAGACTGTGGGCCAGAG aGAA-AAA AGCCCTGCACTCAATTCTGAATGCTGCCATCATGA TCATGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGC 4117 CCACAGTCTCGGTATCTT C TGTGAATGGGGTATAGATTCTACA ATAAAACAAACACAAAAGCCCTAGGTCAGTGTTAAT CATTCACA G AAGATACC 4118 GGTATCTT C TGTGAATG 4119 Alzheimer disease GACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAATCTATACCC 14120 Glu123Lys CATTCACAGAAGATACC G AGACTGTGGGCCAGAGAGCCCTGT cGAG-AAG CACTCAATTCTGAATGCTGCCATCATGATCACTGTCA TGACACTGATCATGATGGCAGCATTCAGAATTGAGTGCAGGG 4121 CTCTCTGGCCCACAGTCT C GGTATCTTCTGTGAATGGGGTAT AGATTCTACAATAAAACAAACACAAAAGCCCTAGGTC AAGATACC G AGACTGTG 4122 CACAGTCT C GGTATCTT 4123 Alzheimer disease TATACCCCATTCACAGAAGATACCGAGACTGTGGGCCAGAGA 4124 Asn13SAsp GCCCTGCACTCAATTCTG A ATGCTGCCATCATGATCAGTGTC gAAT-GAT ATTGTTGTCATGACTATCCTCCTGGTGGTTCTGTATA TATACAGAACCACCAGGAGGATAGTCATGACAACAATGACAC 4125 TGATCATGATGGCAGCAT T CAGAATTGAGTGCAGGGCTCTCT GGCCCACAGTCTCGGTATCTTCTGTGAATGGGGTATA CAATTCTG A ATGCTGCC 4126 GGCAGCAT T CAGAATTG 4127 Alzheimer disease AGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTCAA 4128 Met139Ile TTCTGAATGCTGCCATCAT G ATCAGTGTCATTGTTGTCATGAC ATGa-ATA TATCCTCCTGGTGGTTCTGTATAAATACAGGTGCTAT ATAGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATG 4129 ACAACAATGACACTGAT C ATGATGGCAGCATTCAGAATTGAGT GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCT GCCATCAT G ATCAGTGT 4130 ACACTGAT C ATGATGGC 4131 Alzheimer disease CAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTCA 4132 Met139Lys ATTCTGAATGCTGCCATCA T GATCAGTGTCATTGTTGTCATGA ATG-AAG CTATCCTCCTGGTGGTTCTGTATAAATACAGGTGCTA TAGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATGA 4133 CAACAATGACACTGATC A TGATGGCAGCATTCAGAATTGAGT GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCTG TGCCATCA T GATCAGTG 4134 CACTGATC A TGATGGCA 4135 Alzheimer disease CAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTCA 4136 Met139Thr ATTCTGAATGCTGCCATCA T GATCAGTGTCATTGTTGTCATGA ATG-ACG CTATCCTCCTGGTGGTTCTGTATAAATACAGGTGCTA TAGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATGA 4137 CAACAATGACACTGATC A TGATGGCAGCATTCAGAATTGAGT GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCTG TGCCATCA T GATCAGTG 4138 CACTGATC A TGATGGCA 4139 Alzheimer disease ACAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTC 4140 Met139Val AATTCTGAATGCTGCCATCA T GATCAGTGTCATTGTTGTCATG cATG-GTG ACTATCCTCCTGGTGGTTCTGTATAAATACAGGTGCT AGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATGA 4141 CAACAATGACACTGATCA T GATGGCAGCATTCAGAATTGAGT GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCTGT CTGCCATC A TGATCAGT 4142 ACTGATCA T GATGGCAG 4143 Alzheimer disease GAGACTGTGGGCCAGAGAGCCCTGCACTCAATTCTGAATGCT 4144 Ile143Phe GCCATCATGATCAGTGTC A TTGTTGTCATGACTATCCTCCTGG cATT-TTT TGGTTCTGTATAAATACAGGTGCTATAAGGTGAGCA TGCTCACCTTATAGCACCTGTATTTATACAGAACCACCAGGAG 4145 GATAGTCATGACAACAA T GACACTGATCATGATGGCAGCATTC AGAATTGAGTGCAGGGCTCTCTGGCCCACAGTCTC TCAGTGTC A TTGTTGTC 4146 GACAACAA T GACACTGA 4147 Alzheimer disease AGACTGTGGGCCAGAGAGCCCTGCACTCAATTCTGAATGCTG 4148 Ile143Thr CCATCATGATCAGTGTCA T TGTTGTCATGACTATCCTCCTGGT ATT-ACT GGTTCTGTATAAATACAGGTGCTATAAGGTGAGCAT ATGCTCACCTTATAGCACCTGTATTTATACAGAACCACCAGGA 4149 GGATAGTCATGACAACA A TGACACTGATCATGATGGCAGCAT TCAGAATTGAGTGCAGGGCTCTCTGGCCCACAGTCT CAGTGTCA T TGTTGTCA 4150 TGACAACA A TGACACTG 4151 Alzheimer disease CCAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATGAT 4152 Met146Ile CAGTGTCATTGTTGTCAT G ACTATCCTCCTGGTGGTTCTGTAT ATGa-ATA AAATACAGGTGCTATAAGGTGAGCATGAGACACAGA TCTGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGA 4153 ACCACCAGGAGGATAGT C ATGACAACAATGACACTGATCATG ATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGG GTTGTCAT G ACTATCCT 4154 AGGATAGT C ATGACAAC 4155 Alzheimer disease CCAGAGAGCCCTGCACTCAATTCTGAATGGTGCCATCATGAT 4156 Met146Ile CAGTGTCATTGTTGTCAT G ACTATCCTCCTGGTGGTTCTGTAT ATGa-ATC AAATACAGGTGCTATAAGGTGAGCATGAGACACAGA TCTGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGA 4157 ACCACCAGGAGGATAGT C ATGACAACAATGACACTGATCATG ATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGG GTTGTCAT G ACTATCCT 4158 AGGATAGT C ATGACAAC 4159 Alzheimer disease GGCCAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATG 4160 Met146Leu ATCAGTGTCATTGTTGTC A TGACTATCCTCCTGGTGGTTCTGT cATG-UG ATAAATACAGGTGCTATAAGGTGAGCATGAGACACA TGTGTCTCATGCTCACCUATAGCACCTGTATTTATACAGAAC 4161 CACCAGGAGGATAGTCA T GACAACAATGACACTGATCATGAT GGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGCC TTGTTGTC A TGACTATC 4162 GATAGTCA T GACAACAA 4163 Alzheimer disease GGCCAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATG 4164 Met146Val ATCAGTGTCATTGTTGTC A TGACTATCCTCCTGGTGGTTCTGT cATG-GTG ATAAATACAGGTGCTATAAGGTGAGCATGAGACACA TGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGAAC 4165 CACCAGGAGGATAGTCA T GACAACAATGACACTGATCATGAT GGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGCC TTGTTGTC A TGACTATC 4166 GATAGTCA T GACAACAA 4167 Alzheimer disease AGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATGATCA 4168 Thr147Ile GTGTCATTGTTGTCATGA C TATCCTCCTGGTGGTTCTGTATAA ACT-ATT ATACAGGTGCTATAAGGTGAGCATGAGACACAGATC GATCTGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACA 4169 GAACCACCAGGAGGATA G TCATGACAACAATGACACTGATCA TGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCT TGTCATGA C TATCCTCC 4170 GGAGGATA G TCATGACA 4171 Alzheimer disease CTTTTTAAGGGTTGTGGGACCTGTTAATTATATTGAAATGCTTT 4172 His163Arg CTTTTCTAGGTCATCC A TGCCTGGCTTATTATATCATCTCTATT CAT-CGT GTTGCTGTTCTTTTTTTCATTCATTTACTTGGG CCCAAGTAAATGAATGAAAAAAAGAACAGCAACAATAGAGATG 4173 ATATAATAAGCCAGGCA T GGATGACCTAGAAAAGAAAGCATTT CAATATAATTAACAGGTCCCACAACCCTTAAAAAG GGTCATCC A TGCCTGGC 4174 GCCAGGCA T GGATGACC 4175 Alzheimer disease ACTTTTTAAGGGTTGTGGGACCTGTTAATTATATTGAAATGCTT 4176 His163Tyr TCTTTTCTAGGTCATC C ATGCCTGGCTTATTATATCATCTCTAT cCAT-TAT TGTTGCTGTTTCTTTTTTTCATTCATTTACTTGG CCAAGTAAATGAATGAAAAAAAGAACAGCAACAATAGAGATGA 4177 TATAATAAGCCAGGCAT G GATGACCTAGAAAAGAAAGCATTTC AATATAATTAACAGGTCCCACAACCCTTAAAAAGT AGGTCATC C ATGCCTGG 4178 CCAGGCAT G GATGACCT 4179 Alzheimer disease AGGGTTGTGGGACCTGTTAATTATATTGAAATGCTTTCTTTTCT 4180 Trp165Cys AGGTCATCCATGCCTG G CTTATTATATCATCTCTATTGTTGCT TGGc-TGC GTTCTTTTTTTCATTCATTTACTTGGGGTAAGTT AACTTACCCCAAGTAAATGAATGAAAAAAAGAACAGCAACAAT 4181 AGAGATGATATAATAAG C CAGGCATGGATGACCTAGAAAAGA AAGCATTTCAATATAATTAACAGGTCCCACAACCCT CATGCCTG G CTTATTAT 4182 ATAATAAG C CAGGCATG 4183 Alzheimer disease ACCTGTTAATTATATTGAAATGCTTTCTTTTCTAGGTCATCCAT 4184 Ser169Leu GCCTGGCTTATTATAT C ATCTCTATTGTTGCTGTTCTTTTTTTC TCA-TTA ATTCATTTACTTGGGGTAAGTTGTGAAATTTTT AAAAATTTCACAACTTACCCCAAGTAAATGAATGAAAAAAAGAA 4185 CAGCAACAATAGAGAT G ATATAATAAGCCAGGCATGGATGAC CTAGAAAAGAAAGCATTTCAATATAATTAACAGGT TATTATAT C ATCTCTAT 4186 ATAGAGAT G ATATAATA 4187 Alzheimer disease TAATTATATTGAAATGCTTTCTTTTCTAGGTCATCCATGCCTGG 4188 Leu171Pro CTTATTATATCATCTC T ATTGTTGCTGTTCTTTTTTTCATTCATT CTA-CCA TACTTGGGGTAAGTTGTGAAATTTTTGGTCTG CAGACCAAAAATTTCACAACTTACCCCAAGTAAATGAATGAAA 4189 AAAAGAACAGCAACAAT A GAGATGATATAATAAGCCAGGCAT GGATGACCTAGAAAAGAAAGCATTTCAATATAATTA ATCATCTC T ATTGTTGC 4190 GCAACAAT A GAGATGAT 4191 Alzheimer disease TATTGAAATGCTTTCTTTTCTAGGTCATCCATGCCTGGCTTATT 4192 Leu173Trp ATATCATCTCTAT T GTTGCTGTTCTTTTTTTCATTCATTTACTTG TTG-TGG GGGTAAGTTGTGAAATTTTTGGTCTGTCTTTC GAAAGACAGACCAAAAATTTCACAACTTACCCCAAGTAAATGA 4193 ATGAAAAAAAGAACAGC A ACAATAGAGATGATATAATAAGCCA GGCATGGATGACCTAGAAAAGAAAGCATTCAATA TCTATTGT T GCTGTTCT 4194 AGAACAGC A ACAATAGA 4195 Alzheimer disease TATAACGTTGCTGTGGACTACATTACTGTTGCACTCCTGATCT 4196 Gly209Arg GGAATTTTGGTGTGGTG G GAATGATTTCCATTCACTGGAAAG gGGA-AGA GTCCACTTCGACTCCAGCAGGCATATCTCATTATGA TCATAATGAGATATGCCTGCTGGAGTCGAAGTGGACCTTTCC 4197 AGTGAATGGAAATCATTC C CACCACACCAAAATTCCAGATCAG GAGTGCAACAGTAATGTAGTCCACAGCAACGTTATA GTGTGGTG G GAATGATT 4198 AATCATTC C CACCACAC 4199 Alzheimer disease ATAACGTTGCTGTGGACTACATTACTGTTGCACTCCTGATCTG 4200 Gly209Val GAATTTTGGTGTGGTGG G AATGATTTCCATTCACTGGAAAGGT GGA-GTA CCACTTCGACTCCAGCAGGCATATCTCATTATGAT ATCATAATGAGATATGCCTGCTGGAGTCGAAGTGGACCTTTC 4201 CAGTGAATGGAAATCATT C CCACCACACCAAAATTCCAGATCA GGAGTGCAACAGTAATGTAGTCCACAGCAACGTTAT TGTGGTGG G AATGATTT 4202 AAATCATT C CCACCACA 4203 Alzheimer disease TGGACTACATTACTGTTGCACTCCTGATCTGGAATTTTGGTGT 4204 Ile213Thr GGTGGGAATGATTTCCA T TCACTGGAAAGGTCCACTTCGACT ATT-ACT CCAGCAGGCATATCTCATTATGATTAGTGCCCTCAT ATGAGGGCACTAATCATAATGAGATATGCCTGCTGGAGTCGA 4205 AGTGGACCTTTCCAGTGA A TGGAAATCATTCCCACCACACCA AAATTCCAGATCAGGAGTGCAACAGTAATGTAGTCCA GATTTCCA T TCACTGGA 4206 TCCAGTGA A TGGAAATC 4207 Alzheimer disease CACTCCTGATCTGGAATTTTGGTGTGGTGGGAATGATTTCCAT 4208 Leu219Pro TCACTGGAAAGGTCCAC T TCGACTCCAGCAGGCATATCTCAT CTT-CCT TATGATTAGTGCCCTCATGGCCCTGGTGTTTATCAA TTGATAAACACCAGGGCCATGAGGGCACTAATCATAATGAGA 4209 TATGCCTGCTGGAGTCGA A GTGGACCTTTCCAGTGAATGGAA ATCATTCCCACCACACCAAAATTCCAGATCAGGAGTG AGGTCCAC T TCGACTCC 4210 GGAGTCGA A GTGGACCT 4211 Alzheimer disease ATTTCCATTCACTGGAAAGGTCCACTTCGACTCCAGCAGGCA 4212 Ala231Thr TATCTCATTATGATTAGT G CCCTCATGGCCCTGGTGTTTATCA tGCC-ACC AGTACCTCCCTGAATGGACTGCGTGGCTCATCTTGG CCAAGATGAGCCACGCAGTCCATTCAGGGAGGTACTTGATAA 4213 ACACCAGGGCCATGAGGG C ACTAATCATAATGAGATATGCCT GCTGGAGTCGAAGTGGACCTTTCCAGTGAATGGAAAT TGATTAGT G CCCTCATG 4214 CATGAGGG C ACTAATCA 4215 Alzheimer disease TTTCCATTCACTGGAAAGGTCCACTTCGACTCCAGCAGGCAT 4216 Ala231Val ATCTCATTATGATTAGTG C CCTCATGGCCCTGGTGTTTATCAA GCC-GTC GTACCTCCCTGAATGGACTGCGTGGCTCATCTTGGC GCCAAGATGAGCCACGCAGTCCATTCAGGGAGGTACTTGATA 4217 AACACCAGGGCCATGAGG G CACTAATCATAATGAGATATGCC TGCTGGAGTCGAAGTGGACCTTTCCAGTGAATGGAAA GATTAGTG C CCTCATGG 4218 CCATGAGG G CACTAATC 4219 Alzheimer disease TTCACTGGAAAGGTCCACTTCGACTCCAGCAGGCATATCTCA 4220 Met233Thr TTATGATTAGTGCCCTCA T GGCCCTGGTGTTTATCAAGTACCT ATG-ACG CCCTGAATGGACTGCGTGGCTCATCTTGGCTGTGAT ATCACAGCCAAGATGAGCCACGCAGTCCATTCAGGGAGGTAC 4221 TTGATAAACACCAGGGCC A TGAGGGCACTAATCATAATGAGA TATGCCTGCTGGAGTCGAAGTGGACCTTCCAGTGAA TGCCCTCA T GGCCCTGG 4222 CCAGGGCC A TGAGGGCA 4223 Alzheimer disease GGAAAGGTCCACTTCGACTCCAGCAGGCATATCTCATTATGA 4224 Leu235Pro TTAGTGCCCTCATGGCCC T GGTGTTTATCAAGTACCTCCCTG CTG-CCG AATGGACTGCGTGGCTCATCTTGGCTGTGATTTCAGT ACTGAAATCACAGCCAAGATGAGCCACGCAGTCCATTCAGGG 4225 AGGTACTTGATAAACACC A GGGCCATGAGGGCACTAATCATA ATGAGATATGCCTGCTGGAGTCGAAGTGGACCTTTCC CATGGCCC T GGTGTTTA 4226 TAAACACC A GGGCCATG 4227 Alzheimer disease TCATTATGATTAGTGCCCTCATGGCCCTGGTGTTTATCAAGTA 4228 Ala246Glu CCTCCCTGAATGGACTG C GTGGCTCATCTTGGCTGTGATTTC GCG-GAG AGTATATGGTAAAACCCAAGACTGATAATTTGTTTG CAAACAAATTATCAGTCTTGGGTTTTACCATATACTGAAATCAC 4229 AGCCAAGATGAGCCAC G CAGTCCATTCAGGGAGGTACTTGAT AAACACCAGGGCCATGAGGGCACTAATCATAATGA ATGGACTG C GTGGCTCA 4230 TGAGCCACGCAGTCCAT 4231 Alzheimer disease GTGCCCTCATGGCCCTGGTGTTTATCAAGTACCTCCCTGAAT 4232 Leu250Ser GGACTGCGTGGCTCATCT T GGCTGTGATTTCAGTATATGGTA TTG-TCG AAACCCAAGACTGATAATTTGTTTGTCACAGGAATGC GCATTCCTGTGACAAACAAATTATCAGTCTTGGGTTTTACCAT 4233 ATACTGAAATCACAGCC A AGATGAGCCACGCAGTCCATTCAG GGAGGTACTTGATAAACACCAGGGCCATGAGGGCAC GCTCATCT T GGCTGTGA 4234 TCACAGCC A AGATGAGC 4235 Alzheimer disease AGTTTAGCCCATACATTTTATTAGATGTCTTTTATGTTTTTCTTT 4236 Ala260Val TTCTAGATTTAGTGG C TGTTTTGTGTCCGAAAGGTCCACTTCG GCT-GTT TATGCTGGTTGAAACAGCTCAGGAGAGAAATGA TCATTTCTCTCCTGAGCTGTTTCAACCAGCATACGAAGTGGAC 4237 CTTTCGGACACAAAACA G CCACTAAATCTAGAAAAAGAAAAAC ATAAAAGACATCTAATAAAATGTATGGGCTAAACT TTTAGTGG C TGTTTTGT 4238 ACAAAACA G CCACTAAA 4239 Alzheimer disease CCCATACATTTTATTAGATGTCTTTTATGTTTTTCTTTTTCTAGA 4240 Leu262Phe TTTAGTGGCTGTTTT G TGTCCGAAAGGTCCACTTCGTATGCTG TTGt-TTC GTTGAAACAGCTCAGGAGAGAAATGAAACGCTT AAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACCAGCATACGA 4241 AGTGGACCTTTCGGACA C AAAACAGCCACTAAATCTAGAAAAA GAAAAACATAAAAGACATCTAATAAAATGTATGGG GCTGTTTT G TGTCCGAA 4242 TTCGGACA C AAAACAGC 4243 Alzheimer disease CCATACATTTTATTAGATGTCTTTTATGTTTTCTTTTTCTAGAT 4244 Cys263Arg TTAGTGGCTGTTTTG T GTCCGAAAGGTCCACTTCGTATGCTG gTGT-CGT GTTGAAACAGCTCAGGAGAGAAATGAAACGCTTT AAAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACCAGCATACG 4245 AAGTGGACCTTTCGGAC A CAAAACAGCCACTAAATCTAGAAA AAGAAAAACATAAAAGACATCTAATAAAATGTATGG CTGTTTTGTG T CCGAAA 4246 TTTCGGAC A CAAAACAG 4247 Alzheimer disease ACATTTTATTAGATGTCTTTTATGTTTTTCTTTTTCTAGATTTAG 4248 Pro264Leu TGGCTGTTTTGTGTC C GAAAGGTCCACTTCGTATGCTGGTTG CCG-CTG AAACAGCTCAGGAGAGAAATGAAACGCTTTTTCC GGAAAAAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACCAGCA 4249 TACGAAGTGGACCTTTC G GACACAAAACAGCCACTAAATCTA GAAAAAGAAAAACATAAAAGACATCTAATAAAATGT TTTGTGTC C GAAAGGTC 4250 GACCTTTC G GACACAAA 4251 Alzheimer disease GTCTTTTATGTTTTTCTTTTTCTAGATTTAGTGGCTGTTTTGTG 4252 Arg269Gly TCCGAAAGGTCCACTT C GTATGCTGGTTGAAACAGCTCAGGA tCGT-GGT GAGAAATGAAACGCTTTTTCCAGCTCTCATTTACT AGTAAATGAGAGCTGGAAAAAGCGTTTCATTTCTCTCCTGAGC 4253 TGTTTCAACCAGCATAC G AAGTGGACCTTTCGGACACAAAAC AGCCACTAAATCTAGAAAAAGAAAAACATAAAAGAC GTCCACTT C GTATGCTG 4254 CAGCATAC G AAGTGGAC 4255 Alzheimer disease TCTTTTATGTTTTTCTTTTTCTAGATTTAGTGGCTGTTTTGTGTC 4256 Arg269His CGAAAGGTCCACTTC G TATGCTGGTTGAAACAGCTCAGGAGA CGT-CAT GAAATGAAACGCTTTTTCCAGCTCTCATTTACTC GAGTAAATGAGAGCTGGAAAAAGCGTTTCATTTCTCTCCTGAG 4257 CTGTTTCAACCAGCATA C GAAGTGGACCTTTCGGACACAAAA CAGCCACTAAATCTAGAAAAAGAAAAACATAAAAGA TCCACTTC G TATGCTGG 4258 CCAGCATA C GAAGTGGA 4259 Alzheimer disease TAGTGGCTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTGG 4260 Arg278Thr TTGAAACAGCTCAGGAGA G AAATGAAACGCTTTTTCCAGCTCT AGA-ACA CATTTACTCCTGTAAGTATTTGAGAATGATATTGAA TTCAATATCATTCTCAAATACTTACAGGAGTAAATGAGAGCTG 4261 GAAAAAGCGTTTCATTT C TCTCCTGAGCTGTTTCAACCAGCAT ACGAAGTGGACCTTTCGGACACAAAACAGCCACTA TCAGGAGA G AAATGAAA 4262 TTTCATTT C TCTCCTGA 4263 Alzheimer disease CTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTGGTTGAAAC 4264 Glu280Ala AGCTCAGGAGAGAAATG A AACGCTTTTTCCAGCTCTCATTTAC GAA-GCA TCCTGTAAGTATTTGAGAATGATATTGAATTAGTA TACTAATTCAATATCATTCTCAAATACTTACAGGAGTAAATGAG 4265 AGCTGGAAAAAGCGTT T CATTTCTCTCCTGAGCTGTTTCAACC AGCATACGAAGTGGACCTTTCGGACACAAAACAG GAGAAATG A AACGCTTT 4266 AAAGCGTT T CATTTCTC 4267 Alzheimer disease CTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTGGTTGAAAC 4268 Glu280Gly AGCTCAGGAGAGAAATG A AACGCTTTTTCCAGCTCTCATTTAC GAA-GGA TCCTGTAAGTATTTGAGAATGATATTGAATTAGTA TACTAATTCAATATCATTCTCAAATACTTACAGGAGTAAATGAG 4269 AGCTGGAAAAAGCGTT T CATTTCTCTCCTGAGCTGTTTCAACC AGCATACGAAGTGGACCTTTCGGACACAAAACAG GAGAAATG A AACGCTTT 4270 AAAGCGTT T CATTTCTC 4271 Alzheimer disease TGTGTCCGAAAGGTCCACTTCGTATGCTGGTTGAAACAGCTC 4272 Leu282Arg AGGAGAGAAATGAAACGC T TTTTCCAGCTCTCATTTACTCCTG CTT-CGT TAAGTATTTGAGAATGATATTGAATTAGTAATCAGT ACTGATTACTAATTCAATATCATTCTCAAATACTTACAGGAGTA 4273 AATGAGAGCTGGAAAA A GCGTTTCATTTCTCTCCTGAGCTGTT TCAACCAGCATACGAAGTGGACCTTTCGGACACA TGAAACGC T TTTTCCAG 4274 CTGGAAAA A GCGTTTCA Alzheimer disease AAGGTCCACTTCGTATGCTGGTTGAAACAGCTCAGGAGAGAA 4276 ATa285Val ATGAAACGCTTTTTCCAG C TCTCATTTACTCCTGTAAGTATTTG GCT-GTT AGAATGATATTGAATTAGTAATCAGTGTAGAATTT AAATTCTACACTGATTACTAATTCAATATCATTCTCAAATACTTA 4277 CAGGAGTAAATGAGA G CTGGAAAAAGCGTTTCATTTCTCTCCT GAGCTGTTTCAACCAGCATACGAAGTGGACCTT TTTTCCAG C TCTCATTT 4278 AAATGAGA G CTGGAAAA 4279 Alzheimer disease GGTCCACTTCGTATGCTGGTTGAAACAGCTCAGGAGAGAAAT 4280 Leu286Val GAAACGCTTTTTCCAGCT C TCATTTACTCCTGTAAGTATTTGA tCTC-GTC GAATGATATTGAATTAGTAATCAGTGTAGAATTTAT ATAAATTCTACACTGATTACTAATTCAATATCATTCTCAAATACT 4281 TACAGGAGTAAATGA G AGCTGGAAAAAGCGTTTCATTTCTCTC CTGAGCTGTTTCAACCAGCATACGAAGTGGACC TTCCAGCT C TCATTTAC 4282 GTAAATGA G AGCTGGAA 4283 Alzheimer disease GTGACCAACTTTTTAATATTTGTAACCTTTCCTTTTTAGGGGGA 4284 Gly384Ala GTAAAACTTGGATTGG G AGATTTCATTTTCTACAGTGTTCTGG GGA-GCA TTGGTAAAGCCTCAGCAACAGCCAGTGGAGACTG CAGTCTCCACTGGCTGTTGCTGAGGCTTTACCAACCAGAACA 4285 CTGTAGAAAATGAAATCT C CCAATCCAAGTTTTACTCCCCCTA AAAAGGAAAGGTTACAAATATTAAAAAGTTGGTCAC TGGATTGG G AGATTTCA 4286 TGAAATCT C CCAATCCA 4287 Alzheimer disease TTTGTAACCTTTCCTTTTTAGGGGGAGTAAAACTTGGATTGGG 4288 Ser390Ile AGATTTCATTTTCTACA G TGTTCTGGTTGGTAAAGCCTCAGCA AGT-ATT ACAGCCAGTGGAGACTGGAACACAACCATAGCCTG CAGGCTATGGTTGTGTTCCAGTCTCCACTGGCTGTTGCTGAG 4289 GCTTTACCAACCAGAACA C TGTAGAAAATGAAATCTCCCAATC CAAGTTTTACTCCCCCTAAAAAGGAAAGGTTACAAA TTTCTACA G TGTTCTGG 4290 CCAGAACA C TGTAGAAA 4291 Alzheimer disease AACCTTTCCTTTTTAGGGGGAGTAAAACTTGGATTGGGAGATT 4292 Leu392Val TCATTTTCTACAGTGTT C TGGTTGGTAAAGCCTCAGCAACAGC tCTG-GTG CAGTGGAGACTGGAACACAACCATAGCCTGTTTCG CGAAACAGGCTATGGTTGTGTTCCAGTCTCCACTGGCTGTTG 4293 CTGAGGCTTTACCAACCA G AACACTGTAGAAAATGAAATCTCC CAATCCAAGTTTTACTCCCCCTAAAAAGGAAAGGTT ACAGTGTT C TGGTTGGT 4294 ACCAACCA G AACACTGT 4295 Alzheimer disease ATTTCATTTTCTACAGTGTTCTGGTTGGTAAAGCCTCAGCAAC 4296 Asn405Ser AGCCAGTGGAGACTGGA A CACAACCATAGCCTGTTTCGTAGC AAC-AGC CATATTAATTGTAAGTATACACTAATAAGAATGTGT ACACATTCTTATTAGTGTATACTTACAATTAATATGGCTACGAA 4297 ACAGGCTATGGTTGTG T TCCAGTCTCCACTGGCTGTTGCTGA GGCTTTACCAACCAGAACACTGTAGAAAATGAAAT AGACTGGA A CACAACCA 4298 TGGTTGTG T TCCAGTCT 4299 Alzheimer disease TACAGTGTTCTGGTTGGTAAAGCCTCAGCAACAGCCAGTGGA 4300 Ala409Thr GACTGGAACACAACCATA G CCTGTTTCGTAGCCATATTAATTG aGCC-ACC TAAGTATACACTAATAAGAATGTGTCAGAGCTCTTA TAAGAGCTCTGACACATTCTTATTAGTGTATACTTACAATTAAT 4301 ATGGCTACGAAACAGG C TATGGTTGTGTTCCAGTCTCCACTG GCTGTTGCTGAGGCTTTACCAACCAGAACACTGTA CAACCATA G CCTGTTTC 4302 GAAACAGG C TATGGTTG 4303 Alzheimer disease GTGTTCTGGTTGGTAAAGCCTCAGCAACAGCCAGTGGAGACT 4304 Cys410Tyr GGAACACAACCATAGCCT G TTTCGTAGCCATATTAATTGTAAG TGT-TAT TATACACTAATAAGAATGTGTCAGAGCTCTTAATGT ACATTAAGAGCTCTGACACATTCTTATTAGTGTATACUACAAT 4305 TAATATGGCTACGAAA C AGGCTATGGTTGTGTTCCAGTCTCCA CTGGCTGTTGCTGAGGCTTTACCAACCAGAACAC CATAGCCT G TTTCGTAG 4306 CTACGAAA C AGGCTATG 4307 Alzheimer disease TGTGAATGTGTGTCTTTCCCATCTTCTCCACAGGGTTTGTGCC 4308 Ala426Pro TTACATTATTACTCCTT G CCATTTTCAAGAAAGCATTGCCAGCT tGCC-CCC CTTCCAATCTCCATCACCTTTGGGCTTGTTTTCT AGAAAACAAGCCCAAAGGTGATGGAGATTGGAAGAGCTGGCA 4309 ATGCTTTCTTGAAAATGG C AAGGAGTAATAATGTAAGGCACAA ACCCTGTGGAGAAGATGGGAAAGACACACATTCACA TACTCCTT G CCATTTTC 4310 GAAAATGG C AAGGAGTA 4311 Alzheimer disease AGGGTTTGTGCCTTACATTATTACTCCTTGCCAVTTTCAAGAA 4312 Pro436Gln AGCATTGCCAGCTCTTC C AATCTCCATCACCTTTGGGCTTGTT CCA-CAA TTCTACTTTGCCACAGATTATCTTGTACAGCCTTT AAAAGGCTGTACAAGATAATCTGTGGCAAAGTAGAAAACAAGC 4313 CCAAAGGTGATGGAGATT G GAAGAGCTGGCAATGCTTTCTTG AAAATGGCAAGGAGTAATAATGTAAGGCACAAACCCT AGCTCTTC C AATCTCCA 4314 TGGAGATT G GAAGAGCT 4315 Alzheimer disease CAGGGTTTGTGCCTTACATTATTACTCCTTGCCATTTTCAAGA 4316 Pro436Ser AAGCATTGCCAGCTCTT C CAATCTCCATCACCTTTGGGCTTGT tCCA-TCA TTTCTACTTTGCCACAGATTATCTTGTACAGCCTT AAGGCTGTACAAGATAATCTGTGGCAAAGTAGAAAACAAGCC 4317 CAAAGGTGATGGAGATTG G AAGAGCTGGCAATGCTTTCTTGA AAATGGCAAGGAGTAATAATGTAAGGCACAAACCCTG CAGCTCTT C CAATCTCC 4318 GGAGATTG G AAGAGCTG 4319

EXAMPLE 25 Alzheimer's Disease—Presenilin-2 (PSEN2)

The attached table discloses the correcting oligonucleotide base sequences for the PSEN2 oligonucleotides of the invention.

TABLE 32 PSEN2 Mutations and Genome-Correcting Oligos ClinicaPhenotype & SEQ ID Mutation Correcting Oligos NO: Alzheimer disease GATGTGGTTTCCCACAGAGAAGCCAGGAGAACGAGGAGGAC 4320 Arg62His GGTGAGGAGGACCCTGACC G CTATGTCTGTAGTGGGGTTCC CGC-CAC CGGGCGGCCGCCAGGCCTGGAGGAAGAGCTGACCCTCAA TTGAGGGTCAGCTCTTCCTCCAGGCCTGGCGGCCGCCCGGG 4321 AACCCCACTACAGACATAG C GGTCAGGGTCCTCCTCACCGTC CTCCTCGTTCTCCTGGCTTCTCTGTGGGAAACCACATC CCCTGACC G CTATGTCT 4322 AGACATAG C GGTCAGGG 4323 Alzheimer disease GCCTCGAGGAGCAGTCAGGGCCGGGAGCATCAGCCCTTTGC 4324 Thr122Pro CTTCTCCCTCAGCATCTAC A CGACATTCACTGAGGACACACC cACG-CCG CTCGGTGGGCCAGCGCCTCCTCAACTCCGTGCTGAACA TGTTCAGCACGGAGTTGAGGAGGCGCTGGCCCACCGAGGGT 4325 GTGTCCTCAGTGAATGTCG T GTAGATGCTGAGGGAGAAGGCA AAGGGCTGATGCTCCCGGCCCTGACTGCTCCTCGAGGC GCATCTAC A CGACATTC 4326 GAATGTCG T GTAGATGC 4327 Alzheimer disease ACACGCCATTCACTGAGGACACACCCTCGGTGGGCCAGCGC 4328 Asn141Ile CTCCTCAACTCCGTGCTGA A CAGCCTCATCATGATCAGCGTC AAC-ATC ATCGTGGTTATGACCATCTTCTTGGTGGTGCTCTACAA TTGTAGAGCACCACCAAGAAGATGGTCATAACCACGATGACG 4329 CTGATCATGATGAGGGTG T TCAGCACGGAGTTGAGGAGGCG CTGGCCCACCGAGGGTGTGTCCTCAGTGAATGGCGTGT CGTGCTGA A CACCCTCA 4330 TGAGGGTG T TCAGCACG 4331 Alzheimer disease CCACTGGAAGGGCCCTCTGGTGCTGCAGCAGGCCTACCTCA 4332 Met239Ile TCATGATCAGTGCGCTCAT G GCCCTAGTGTTCATCAAGTACCT ATGg-ATA CCCAGAGTGGTCCGCGTGGGTCATCCTGGGCGCCATC GATGGCGCCCAGGATGACCCACGCGGACCACTCTGGGAGGT 4333 ACTTGATGAACACTAGGGC C ATGAGCGCACTGATCATGATGA GGTAGGCCTGCTGCAGCACCAGAGGGCCCTTCCAGTGG GCGCTCAT G GCCCTAGT 4334 ACTAGGGC C ATGAGCGC 4335 Alzheimer disease ATCCACTGGAAGGGCCCTCTGGTGCTGCAGCAGGCCTACCT 4336 Met239Val CATCATGATCAGTGCGCTC A TGGCCCTAGTGTTCATCAAGTA cATG-GTG CCTCCCAGAGTGGTCCGCGTGGGTCATCCTGGGCGCCA TGGCGCCCAGGATGACCCACGCGGACCACTCTGGGAGGTAC 4337 TTGATGAACACTAGGGCCA T GAGCGCACTGATCATGATGAGG TAGGCCTGCTGCAGCACCAGAGGGCCCTTCCAGTGGAT GTGCGCTC A TGGCCCTA 4338 TAGGGCCA T GAGCGCAC 4339

EXAMPLE 26 Plant Cells

The oligonucleotides of the invention can also be used to repair or direct a mutagenic event in plants and animal cells. Although little information is available on plant mutations amongst natural cultivars, the oligonucleotides of the invention can be used to produce “knock out” mutations by modification of specific amino acid codons to produce stop codons (e.g., a CAA codon specifying Gln can be modified at a specific site to TAA; a MG codon specifying Lys can be modified to UAG at a specific site; and a CGA codon for Arg can be modified to a UGA codon at a specific site). Such base pair changes will terminate the reading frame and produce a defective truncated protein, shortened at the site of the stop codon. Alternatively, frameshift additions or deletions can be directed into the genome at a specific sequence to interrupt the reading frame and produce a garbled downstream protein. Such stop or frameshift mutations can be introduced to determine the effect of knocking out the protein in either plant or animal cells.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. 

1. A method of optimizing an oligonucleotide for in vitro targeted chromosomal sequence alteration, comprising: (a) Providing a first oligonucleotide and a second oligonucleotide for alteration of a targeted nucleic acid sequence, i) wherein said first oligonucleotide: (1) is a single-stranded nonhairpin oligonucleotide 17-121 nucleotides in length, (2) has an unmodified DNA domain of at least 8 contiguous deoxyribonucleotides, (3) is fully complementary in sequence to the sequence of a first strand of the nucleic acid target but for one or more mismatches as between the sequences of said deoxyribonucleotides domain and its complement on the target nucleic acid first strand, each of said mismatches positioned at least 8 nucleotides from said first oligonucleotide's 5′ and 3′ termini, and (4) has at least one terminal modification selected from the group consisting of: at least one terminal locked nucleic acid (LNA), at least one terminal 2′-O-Me base analog, and at least three terminal phophorothioate linkages, and ii) wherein said second oligonucleotide is selected from the group consisting of (1) an oligonucleotide that is fully complementary to the target and lacks the mismatch, (2) a fully modified phosphothiolated oligonucleotide, (3) a fully modified 2′-O-methylated oligonucleotide, and (4) a chimeric double-stranded double hairpin containing RNA and DNA nucleotides, and iii) wherein the targeted nucleic acid sequence alteration is not in human embryonic stem cells; (b) combining the targeted nucleic acid with said first or said second oligonucleotide in the presence of cellular repair proteins; (c) combining the targeted nucleic acid with the other of said first or second oligonucleotide in the presence of cellular repair proteins; (d) quantifying the percentage of target molecules that undergo a sequence alteration event; (e) comparing the efficiency of alteration of said targeted nucleic acid sequence by said first oligonucleotide with the efficiency of alteration of the same targeted nucleic acid sequence by said second oligonucleotide; and (f) repeating steps (a) through (e) two or more times to optimize said first oligonucleotide for in vitro targeted chromosomal sequence alteration.
 2. The method of claim 1, wherein said sequence alteration is a substitution of at least one base.
 3. The method of claim 1, wherein said sequence alteration is a deletion of at least one base.
 4. The method of claim 1, wherein said sequence alteration is an insertion of at least one base.
 5. The method of claim 1, wherein the target nucleic acid is cellular chromosomal DNA.
 6. The method of claim 1, wherein the target nucleic acid is an artificial chromosome.
 7. The method of claim 1, wherein the alteration is produced in a cell.
 8. The method of claim 7, wherein said cell is cultured ex vivo.
 9. The method of claim 1, wherein the alteration is produced in a cell-free extract.
 10. The method of claim 1, wherein said cellular repair proteins are of a cell selected from the group consisting of prokaryotic cells and eukaryotic cells.
 11. The method of claim 10, wherein said cell is a prokaryotic cell.
 12. The method of claim 11, wherein said prokaryotic cell is a bacterial cell.
 13. The method of claim 12, wherein said bacterial cell is an E. coli cell.
 14. The method of claim 10, wherein said cell is a eukaryotic cell.
 15. The method of claim 14, wherein said eukaryotic cell is a yeast cell, plant cell, human cell, or a mammalian cell.
 16. The method of claim 15, wherein said eukaryotic cell is a yeast cell.
 17. The method of claim 16, wherein said yeast cell is a Saccharomyces cerevisiae, Ustilago maydis, or Candida albicans cell.
 18. The method of claim 15, wherein said eukaryotic cell is a plant cell.
 19. The method of claim 15, wherein said eukaryotic cell is a human cell.
 20. The method of claim 19, wherein said human cell is selected from the group consisting of liver cell, lung cell, colon cell, cervical cell, kidney cell, epithelial cell, cancer cell, and stem cell.
 21. The method of claim 15, wherein said eukaryotic cell is from a mammal.
 22. The method of claim 21, wherein said mammal is selected from the group consisting of rodent, mouse, hamster, rat, and monkey.
 23. The method of claim 1, wherein said first oligonucleotide is at least 25 nucleotides in length.
 24. The method of claim 1, wherein said first oligonucleotide is no more than 74 nucleotides in length.
 25. The method of claim 1, wherein said first strand is the nontranscribed strand of the target nucleic acid.
 26. The method of claim 1, wherein the sequences of said deoxyribonucleotides domain and of the target nucleic acid first strand are mismatched at a single nucleotide.
 27. The method of claim 1, wherein the sequences of said deoxyribonucleotides domain and of its complement on the target nucleic acid first strand are mismatched at two or more nucleotides.
 28. The method of claim 1, wherein said at least one terminal modification is at least on 3′ terminal LNA analog.
 29. The method of claim 1, wherein said first oligonucleotide has no more than 3 LNA analogs at its 3′ terminus.
 30. The method of claim 1, wherein said first oligonucleotide has at least one LNA at its 3′ terminus and at least one LNA at its 5′ terminus.
 31. The method of claim 30, wherein said first oligonucleotide has no more than 3 contiguous LNA at each of its 3′ or 5′ termini.
 32. The method of claim 1, wherein said at least one terminal modification is at least one 2′-O-methyl ribonucleotides analog at its 3′ terminus.
 33. The method of claim 32, wherein said first oligonucleotide has no more than 4 contiguous 2′-O-methyl ribonucleotides analogs.
 34. The method of claim 32, wherein said first oligonucleotide has at least one 2′-O-methyl ribonucleotide analog at its 3′ terminus and at least one 2′-O-methyl ribonucleotide analog at its 5′ terminus.
 35. The method of claim 34, wherein said first oligonucleotide has no more than 4 contiguous 2′-O-methyl ribonucleotides analogs.
 36. The method of claim 1, wherein said at least one terminal modification comprises at least three terminal phosphorothioate linkages.
 37. The method of claim 36, wherein said phosphorothioate linkages are at said first oligonucleotide's 3′ terminus.
 38. The method of claim 36, wherein said first oligonucleotide comprises no more than 6 contiguous phosphorothioate linkages.
 39. The method of claim 1, wherein said second oligonucleotide is fully complementary to the target and lacks the mismatch.
 40. The method of claim 1, wherein said second oligonucleotide is a fully modified phosphothiolated oligonucleotide.
 41. The method of claim 1, wherein said second oligonucleotide is a fully modified 2′-O-methylated oligonucleotide.
 42. The method of claim 1, wherein said second oligonucleotide is a chimeric double-stranded double hairpin containing RNA and DNA nucleotides.
 43. A method of optimizing an oligonuoleotide for targeted nucleic acid sequence alteration of a nucleic acid present within selectively enriched cells in vitro, cells in culture, or cell-free extracts, comprising: (a) Providing a first oligonucleotide and a second oligonucleotide for alteration of a targeted nucleic acid sequence, i) wherein said first oligonucleotide: (1) is a single-stranded nonhairpin oligonucleotide 17-121 nucleotides in length, (2) has an unmodified DNA domain of at least 8 contiguous deoxyribonucleotides, (3) is fully complementary in sequence to the sequence of a first strand of the nucleic acid target but for one or more mismatches as between the sequences of said deoxyribonucleotides domain and its complement on the target nucleic acid first strand, each of said mismatches positioned at least 8 nucleotides from said first oligonucleotide's 5′ and 3′ termini, and (4) has at least one terminal modification selected from the group consisting of: at least one terminal locked nucleic acid (LNA), at least one terminal 2′-O-Me base analog, and at least three terminal phophorothioate linkages, and ii) wherein said second oligonucleotide is selected from the group consisting of (1) an oligonucleotide that is fully complementary to the target and lacks the mismatch, (2) a fully modified phosphothiolated oligonucleotide, (3) a fully modified 2′-O-methylated oligonucleotide, and (4) a chimeric double-stranded double hairpin containing RNA and DNA nucleotides, and iii) wherein said cultured or selectively enriched cells are not human embryonic stem cells, and iv) wherein said targeted nucleic acid is selected from the group of human genes consisting of: ADA, p53, beta-globin, RB, BRCA1, BRCA2, CFTR, CDKN2A, APC, Factor V, Factor VIII, Factor IX, hemoglobin alpha 1, hemoglobin alpha 2, MLH1, MSH2, MSH6, ApoE, LDL receptor, UGT1, APP, PSEN1, and PSEN2; (b) combining the targeted nucleic acid with said first or said second oligonucleotide in the presence of cellular repair proteins; (c) combining the targeted nucleic acid with the other of said first or said second oligonucleotide in the presence of cellular repair proteins; (d) quantifying the percentage of target molecules that undergo a sequence alteration event; (e) comparing the efficiency of alteration of said targeted nucleic acid sequence by said first oligonucleotide with the efficiency of alteration of the same targeted nucleic acid sequence by said second oligonucleotide; and (f) repeating steps (a) through (e) two or more times to optimize said first oligonucleotide for targeted nucleic acid sequence alteration.
 44. A method of optimizing an oligonucleotide for targeted sequence alteration of a nucleic acid present within selectively enriched cells in vitro, cells in culture, or cell-free extracts, comprising: (a) Providing a first oligonucleotide and a second oligonucleotide for alteration of a targeted nucleic acid sequence, i) wherein said first oligonucleotide: (1) is a single-stranded nonhairpin oligonucleotide 17-121 nucleotides in length, (2) has an unmodified DNA domain of at least 8 contiguous deoxyribonucleotides, (3) is fully complementary in sequence to the sequence of a first strand of the nucleic acid target but for one or more mismatches as between the sequences of said deoxyribonucleotides domain and its complement on the target nucleic acid first strand, each of said mismatches positioned at least 8 nucleotides from said first oligonucleotide 's 5′ and 3′ termini, and (4) has at least one terminal modification selected from the group consisting of: at least one terminal locked nucleic acid (LNA), at least one terminal 2′-O-Me base analog, and at least three terminal phophorothioate linkages, and ii) wherein said second oligonucleotide is selected from the group consisting of (1) an oligonucleotide that is fully complementary to the target and lacks the mismatch, (2) a fully modified phosphothiolated oligonucleotide, (3) a fully modified 2′-O-methylated oligonucleotide, and (4) a chimeric double-stranded double hairpin containing RNA and DNA nucleotides, and iii) wherein said cultured or selectively enriched cells are not human embryonic stem cells, and iv) wherein said first and second oligonucleotides include the sequence of any one of SEQ ID NOs: 1-4340; (b) combining the targeted nucleic acid with said first or said second oligonucleotide in the presence of cellular repair proteins; (c) combining the targeted nucleic acid with the other of said first or said second oligonucleotide in the presence of cellular repair proteins; (d) quantifying the percentage of target molecules that undergo a sequence alteration event; (e) comparing the efficiency of alteration of said targeted nucleic acid sequence by said first oligonucleotide with the efficiency of alteration of the same targeted nucleic acid sequence by said second oligonucleotide; and (f) repeating steps (a) through (e) two or more times to optimize said first oligonucleotide for targeted sequence alteration of a nucleic acid.
 45. The method of claim 44, wherein said first and second oligonucleotides consist of the sequence of any one of SEQ ID NOs: 1-4340. 